Chemical compounds

ABSTRACT

Compounds of the general structural formula  
                 
 
     and use of the compounds and salts and solvates thereof, as therapeutic agents.

FIELD AND BACKGROUND OF THE INVENTION

[0001] This invention relates to a series of compounds, to methods ofpreparing the compounds, to pharmaceutical compositions containing thecompounds, and to their use as therapeutic agents. In particular, theinvention relates to compounds that are potent and selective inhibitorsof cyclic guanosine 3′,5′-monophosphate specific phosphodiesterase(cGMP-specific PDE), in particular PDE5, and have utility in a varietyof therapeutic areas wherein such inhibition is considered beneficial,including the treatment of cardiovascular disorders and erectiledysfunction.

SUMMARY OF THE INVENTION

[0002] The present invention provides compounds of formula (I)

[0003] wherein R⁰, independently, is selected from the group consistingof halo, C₁₋₆alkyl, aryl, heteroaryl, C₃₋₈cycloalkyl,C₃₋₈heterocycloalkyl, C₃₋₈cycloalkylQ, C(═O)R^(a), OC(═O)R^(a),C(═O)OR^(a), C₁₋₄alkyleneNR^(a)R^(b), C₁₋₄alkyleneHet,C₁₋₄alkyleneC(═O)OR^(a), C(═O)NR^(a)SO₂R^(c), C(═O)C₁₋₄alkyleneHet,C(═O)NR^(a)R^(b), C(═O)NR^(b)R^(c), C(═O)—NR^(a)C₁₋₄alkyleneOR^(b),C(═O)NR^(a)C₁₋₄alkyleneHet, OR^(a), OC₁₋₄-alkyleneC(═O)OR^(a),OC₁₋₄alkyleneNR^(a)R^(b), OC₁₋₄alkyleneHet, OC₁₋₄alkyleneOR^(a),OC₁₋₄alkyleneNR^(a)C(═O)OR^(b), NR^(a)R^(b), NR^(b)R^(c),NR^(a)C₁₋₄alkyleneNR^(a)R^(b), NR^(a)C(═O)R^(b), NR^(a)C(═O)NR^(a)R^(b),N(SO₂C₁₋₄alkyl)₂, NR^(a)(SO₂C₁₋₄alkyl), nitro, trifluoromethyl,trifluoromethoxy, cyano, SO₂NR^(a)R^(b), SO₂R^(a), SOR^(a), SR^(a), andOSO₂CF₃;

[0004] R¹ is selected from the group consisting of optionallysubstituted aryl, optionally substituted heteroaryl, an optionallysubstituted C₃₋₈cycloalkyl ring, an optionally substitutedC₃₋₈heterocycloalkyl ring, an optionally substituted bicyclic ring

[0005] wherein the fused ring B is a 5- or 6-membered ring, saturated orpartially or fully unsaturated, and comprises carbon atoms andoptionally one to three heteroatoms selected from oxygen, sulfur, andnitrogen, hydrogen, C₁₋₆alkyl, arylC₁₋₃alkyl, C₁₋₃alkenylenearyl,haloC₁₋₆alkyl, C₁₋₄alkyleneC(═O)OR^(a), C₁₋₄alkyleneC(═O)NR^(a)R^(b),C₃₋₈cycloalkyl, C₃₋₈cycloalkenyl, C₃₋₈hetero-cycloalkenyl,C₁₋₄alkyleneHet, C₁₋₄alkyleneQR^(a), C₂₋₆-alkenyleneQR^(a),C₁₋₄alkyleneQC₁₋₄alkyleneQR^(a),

[0006] and a spiro substituent having a structure

[0007] R² is selected from the group consisting of hydrogen, C₁₋₆alkyl,C₃₋₈cycloalkyl, C₃₋₈heterocycloalkyl, C₂₋₆alkenyl, C₁₋₃alkylenearyl,arylC₁₋₃alkyl, aryl, heteroaryl, C(═O)R^(a), C(═O)NR^(a)R^(b),C(═O)NR^(b)R^(c), C(═S)NR^(a)R^(b), C(═S)NR^(b)R^(c), OR^(a),NR^(a)R^(b), NR^(b)R^(c), SO₂R^(a), SO₂NR^(a)R^(b), S(═O)R^(a),S(═O)NR^(a)R^(b), C(═O)NR^(a)C₁₋₄alkyleneOR^(a),C(═O)NR^(a)C₁₋₄alkyleneHet, C(═O)C₁₋₄alkylenearyl,C(═O)—C₁₋₄alkyleneheteroaryl, C₁₋₄alkylenearyl, C₁₋₄alkyleneheteroaryl,C₁₋₄alkyleneHet, C₁₋₄alkyleneC(═O)C₁₋₄alkylenearyl,C₁₋₄alkyleneC(═O)C₁₋₄alkyleneheteroaryl, C₁₋₄alkyleneC(═O)Het,C₁₋₄alkyleneC(═O)NR^(b)R^(c), C₁₋₄alkyleneOR^(a),C₁₋₄alkyleneNR^(a)C(═O)R^(a), C₁₋₄alkyleneOC₁₋₄alkyl-eneOR^(a),C₁₋₄alkyleneNR^(b)R^(c), C₁₋₄alkyleneC(═O)OR^(a), andC₁₋₄alkyleneC₁₋₄alkyleneC(═O)OR^(a);

[0008] R³ is selected from the group consisting of hydrogen, C₁₋₆alkyl,haloC₁₋₆alkyl, aryl, heteroaryl, arylC₁₋₃alkyl, heteroarylC₁₋₃alkyl,C₁₋₃alkylenearyl, C₁₋₃alkyleneHet, C₃₋₈cycloalkyl, andC₃₋₈heterocycloalkyl;

[0009] Y is selected from the group consisting of C(═O), C(═O)Z, SO,SO₂, C(═S), C(R^(a))₂, and CR^(a)═CR^(a);

[0010] Z is (CH₂)_(t) or C≡C;

[0011] A is aryl or heteroaryl and is selected from the group consistingof optionally substituted 5- or 6-membered aromatic rings and optionallysubstituted fused bicyclic ring systems, either carbocyclic orcontaining at least one heteroatom selected from the group consisting ofoxygen, nitrogen, and sulfur, and containing at least one aromatic ring;

[0012] R⁴ is selected from the group consisting of hydrogen, C₁₋₆alkyl,aryl, heteroaryl, halo, C(═O)OR^(b), NHC(═O)C₁₋₃alkyleneN(R^(b))₂, NO₂,C(═O)OR^(b), OR^(b), CF₃, OR^(a), CN, OC(═O)R^(b), arylOR^(b), Het,NR^(a)C(═O)C₁₋₃alkyleneC(═O)—OR^(a), arylOC₁₋₃alkyleneNR^(a)R^(b),arylOC(═O)R^(a), C₁₋₄alkylene-C(═O)OR^(b), OC₁₋₄alkyleneC(═O)OR^(b),C₁₋₄alkyleneOC₁₋₄alkyleneC(═O)OR^(b), C(═O)NR^(b)SO₂R^(c),C₁₋₄alkyleneNR^(b)R^(c), C₂₋₆-alkenyleneNR^(b)R^(c),C(═O)NR^(b)C₁₋₄alkyleneOR^(b), C(═O)NR^(b)C₁₋₄-alkyleneHet,OC₂₋₄alkyleneNR^(b)R^(c), OC₁₋₄alkyleneCH(OR^(b))—CH₂NR^(b)R^(c),OC₁₋₄alkyleneHet, OC₂₋₄alkyleneOR^(b), OC₂₋₄alkyleneNR^(b)C(═O)OR^(c),NR^(b)C₁₋₄alkyleneNR^(b)R^(c), NR^(b)C(═O)R^(c), NR^(b)C(═O)NR^(b)R^(c),N(SO₂C₁₋₄alkyl)₂, NR^(b)(SO₂C₁₋₄alkyl), SO₂NR^(b)R^(c), OSO₂CF₃,C(═O)R^(b), C₁₋₃alkylenearyl, C₁₋₄alkyleneHet, C₁₋₆alkyleneOR^(b),C₁₋₃alkyleneN(R^(b))₂, NR^(b)R^(c), C(═O)NR^(b)R^(c),NHC(═O)C₁₋₃alkylenearyl, NHC(═O)C₁₋₃alkyleneheteroaryl, C₃₋₈cycloalkyl,C₃₋₈heterocycloalkyl, arylOC₁₋₃alkyleneN(^(R)b)₂, arylOC(═O)R^(b),NHC(═O)C₁₋₃-alkyleneC₃₋₈heterocycloalkyl, NHC(═O)C₁₋₃alkyleneHet,NHC(═O)haloC₁₋₆alkyl, and

[0013] R⁵, independently, is selected from the group consisting of halo,NR^(a)R^(b), NO₂, C₁₋₆alkyl, oxo, and OR^(a);

[0014] or R⁴ and R⁵ are taken together to form a 3- or 4-memberedalkylene or alkenylene chain component of a 5- or 6-membered ring,optionally containing at least one heteroatom;

[0015] R^(a) is selected from the group consisting of hydrogen,C₁₋₆alkyl, cyano, aryl, arylC₁₋₃alkyl, C₁₋₃-alkylenearyl, heteroaryl,heteroarylC₁₋₃alkyl, and C₁₋₃alkyleneheteroaryl;

[0016] R^(b) is selected from the group consisting of hydrogen,C₁₋₆alkyl, C₃₋₈cycloalkyl, C₁₋₃alkyleneN(R^(a))₂, aryl, arylC₁₋₃alkyl,C₁₋₃alkylenearyl, heteroaryl, heteroarylC₁₋₃alkyl, andC₁₋₃alkyleneheteroaryl;

[0017] R^(c) is selected from the group consisting of hydrogen,C₁₋₆alkyl, aryl, heteroaryl, arylC₁₋₃alkyl, heteroarylC₁₋₃alkyl,C₁₋₃alkyleneN(R^(a))₂, C₁₋₆alkylene-aryl, C₁₋₆alkyleneHet,haloC₁₋₆alkyl, C₃₋₈cycloalkyl, C₃₋₈heterocycloalkyl, Het,C1-3alkyleneheteroaryl, C₁₋₆alkyleneC(═O)OR^(a), andC₁₋₃alkyleneC₃₋₈heterocycloalkyl;

[0018] or R^(b) and R^(c) are taken together to form a 5- or 6-memberedring, optionally containing at least one heteroatom;

[0019] Q is O, S, or NR^(d);

[0020] C is O, S, or NR^(d);

[0021] D is O, S, or NR^(a);

[0022] E is CR^(a) or N;

[0023] F is CR^(a), C(R^(a))₂, or NR^(d);

[0024] R^(d) is null or is selected from the group consisting ofhydrogen, C₁₋₆alkyl, aryl, heteroaryl, arylC₁₋₃alkyl,heteroarylC₁₋₃alkyl, C₁₋₃alkylenearyl, and C₁₋₃alkyleneheteroaryl;

[0025] Het is a 5- or 6-membered heterocyclic ring, saturated orpartially or fully unsaturated, containing at least one heteroatomselected from the group consisting of oxygen, nitrogen, and sulfur, andoptionally substituted with C₁₋₄alkyl or C(═O)OR^(a);

[0026] n is 0 or 1;

[0027] p is 0, 1, 2, or 3;

[0028] q is 0, 1, 2, 3, or 4;

[0029] t is 1, 2, 3, or 4;

[0030] and pharmaceutically acceptable salts and solvates (e.g.,hydrates) thereof.

[0031] In a preferred embodiment, R² and R³ is hydrogen, q is 0, and thecompounds have a structural formula (II):

[0032] wherein R¹ is selected from the group consisting of optionallysubstituted aryl, optionally substituted heteroaryl, an optionallysubstituted bicyclic ring

[0033] wherein the fused ring B is a 5- or 6-membered ring, saturated orpartially or fully unsaturated, and comprises carbon atoms andoptionally one to three heteroatoms selected from oxygen, sulfur, andnitrogen;

[0034] Y null or is selected from the group consisting of C(═O),C(═O)C≡C, C(═O)(CH₂)_(t), SO₂, and C(═S);

[0035] A is aryl or heteroaryl and is selected from the group consistingof optionally substituted 5- or 6-membered aromatic rings and optionallysubstituted fused bicyclic ring systems, either carbocyclic orcontaining at least one heteroatom selected from the group consisting ofoxygen, nitrogen, and sulfur, and containing at least one aromatic ring;

[0036] R⁴ is selected from the group consisting of hydrogen, C₁₋₆alkyl,aryl, heteroaryl, halo, C(═O)OR^(b), NHC(═O)C₁₋₃alkyleneN(R^(b))₂, NO₂,C(═O)OR^(b), OR^(b), CF₃, OR^(a), CN, OC(═O)R^(b), arylOR^(b), Het,NR^(a)C(═O)C₁₋₃alkylene-C(═O)OR^(a), arylOC₁₋₃alkyleneNR^(a)R^(b),arylOC(═O)R^(a), C₁₋₄-alkyleneC(═O)OR^(b), OC₁₋₄alkyleneC(═O)OR^(b),C(═O)NR^(b)SO₂R^(c), C₁₋₄alkyleneNR^(b)R^(c), C₂₆alkenyleneNR^(b)R^(c),C(═O)NR^(b)C₁₋₄-alkyleneOR^(b), NR^(b)C₁₋₄alkyleneNR^(b)R^(c),NR^(b)C(═O)R^(c), NR^(b)C(═O)—NR^(b)R^(c), OSO₂CF₃, C(═O)R^(b),C₁₋₃alkylenearyl, C₁₋₄alkylene-Het, C₁₋₆alkyleneOR^(b),C₁₋₃alkyleneN(R^(b))₂, NR^(b)R^(c), C(═O)—NR^(b)R^(c),NHC(═O)C₁-C₃alkylenearyl, NHC(═O)C₁₋₃alkylene-heteroaryl,NHC(═O)C₁₋₃alkyleneC₃₋₈heterocycloalkyl, NHC(═O)C₁₋₃alkyleneHet,NHC(═O)haloC₁₋₆alkyl, and

[0037] R⁵, independently, is selected from the group consisting of halo,NR^(a)R^(b), NO₂, C₁₋₆alkyl, oxo, and OR^(a);

[0038] R^(a) and R^(b), independently, are selected from the groupconsisting of hydrogen, C₁₋₆alkyl, aryl, arylC₁₋₃alkyl,C₁₋₃alkylenearyl, heteroaryl, hetero-arylC₁₋₃alkyl, andC₁₋₃alkyleneheteroaryl;

[0039] R^(c) is selected from the group consisting of hydrogen,C₁₋₆alkyl, aryl, heteroaryl, arylC₁₋₃alkyl, heteroarylC₁₋₃alkyl,C₁₋₃alkyleneN(R^(a))₂, C₁₋₆alkylenearyl, C₁₋₆alkyleneHet, haloC₁₋₆alkyl,C₃₋₈cycloalkyl, C₃₋₈heterocycloalkyl, Het, C₁₋₃alkyleneheteroaryl,C₁₋₆alkyleneC(═O)OR^(a), and C₁₋₃alkyleneC₃₋₈heterocycloalkyl;

[0040] or R^(b) and R^(c) are taken together to form a 5- or 6-memberedring, optionally containing at least one heteroatom;

[0041] Het is a 5- or 6-membered heterocyclic ring, saturated orpartially or fully unsaturated, containing at least one heteroatomselected from the group consisting of oxygen, nitrogen, and sulfur, andoptionally substituted with C₁₋₄alkyl or C(═O)OR^(a);

[0042] p is 0, 1, 2, or 3;

[0043] t is 1, 2, 3, or 4;

[0044] and pharmaceutically acceptable salts and solvates (e.g.,hydrates) thereof.

[0045] As used herein, the term “alkyl” includes straight chained andbranched hydrocarbon groups containing the indicated number of carbonatoms, typically methyl, ethyl, and straight chain and branched propyland butyl groups. The hydrocarbon group can contain up to 16 carbonatoms. The term “alkyl” includes “bridged alkyl,” i.e., a C₆-C₁₆bicyclic or polycyclic hydrocarbon group, for example, norbornyl,adamantyl, bicyclo[2.2.2]octyl, bicyclo[2.2.]heptyl,bicyclo[3.2.1]octyl, or decahydronaphthyl. The term “cycloalkyl” isdefined as a cyclic C₃-C₈ hydrocarbon group, e.g., cyclopropyl,cyclobutyl, cyclohexyl, and cyclopentyl. “Heterocycloalkyl” is definedsimilarly as cycloalkyl except the ring contains one to threeheteroatoms selected from the group consisting of oxygen, nitrogen, andsulfur.

[0046] The term “alkenyl” is defined identically as “alkyl,” except forcontaining a carbon-carbon double bond. “Cycloalkenyl” is definedsimilarly to cycloalkyl, except a carbon-carbon double bond is presentin the ring.

[0047] The term “alkylene” refers to an alkyl group having asubstituent. For example, the term “C₁₋₃alkylenearyl” refers to an alkylgroup containing one to three carbon atoms, and substituted with an arylgroup. The term “alkenylene” as used herein is similarly defined, andcontains the indicated number of carbon atoms and a carbon-carbon doublebond, and includes straight chained and branched alkenylene groups, likeethyenylene.

[0048] The term “halo” or “halogen” is defined herein to includefluorine, bromine, chlorine, and iodine.

[0049] The term “haloalkyl”, is defined herein as an alkyl groupsubstituted with one or more halo substituents, either fluoro, chloro,bromo, iodo, or combinations thereof. Similarly, “halocycloalkyl” isdefined as a cycloalkyl group having one or more halo substituents.

[0050] The term “aryl,” alone or in combination, is defined herein as amonocyclic or polycyclic aromatic group, preferably a monocyclic orbicyclic aromatic group, e.g., phenyl or naphthyl. Unless otherwiseindicated, an “aryl” group can be unsubstituted or substituted, forexample, with one or more, and in particular one to three, halo, alkyl,hydroxyalkyl, alkoxy, alkoxyalkyl, haloalkyl, nitro, amino, alkylamino,acylamino, alkylthio, NHC(═O)C₁₋₃-alkyl, OC₁₋₃alkyleneNR^(a)R^(b),alkylsulfinyl, and alkylsulfonyl. Exemplary aryl groups include phenyl,naphthyl, tetrahydronaphthyl, 2-chlorophenyl, 3-chlorophenyl,4-chlorophenyl, 2-methylphenyl, 4-methoxyphenyl,3-trifluoromethylphenyl, 4-nitrophenyl, and the like. The terms“arylC₁₋₃alkyl” and “heteroarylC₁₋₃alkyl”, are defined as an aryl orheteroaryl group having a C₁₋₃alkyl substituent.

[0051] The term “heteroaryl” is defined herein as a monocyclic orbicyclic ring system containing one or two aromatic rings and containingat least one nitrogen, oxygen, or sulfur atom in an aromatic ring, andwhich can be unsubstituted or substituted, for example, with one ormore, and in particular one to three, substituents, like halo, alkyl,hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, haloalkyl, nitro, amino,alkylamino, acylamino, alkylthio, alkylsulfinyl, and alkylsulfonyl.Examples of heteroaryl groups include thienyl, furyl, pyridyl, oxazolyl,quinolyl, isoquinolyl, indolyl, triazolyl, isothiazolyl, isoxazolyl,imidizolyl, benzothiazolyl, pyrazinyl, pyrimidinyl, thiazolyl, andthiadiazolyl.

[0052] The term “Het” is defined as a 5- or 6-membered heterocyclecontaining one or more hetero-atoms selected from the group consistingof oxygen, nitrogen, and sulfur. A “Het” group also can contain an oxogroup (═O) attached to the ring. Nonlimiting examples of Het groupsinclude 1,3-dioxolane, 2-pyrazoline, pyrazolidine, pyrrolidine,piperazine, a pyrroline, 2H-pyran, 4H-pyran, morpholine, thiopholine,piperidine, 1,4-dithiane, and 1,4-dioxane.

[0053] The term “hydroxy” is defined as —OH.

[0054] The term “alkoxy” is defined as —OR, wherein R is alkyl.

[0055] The term “alkoxyalkyl” is defined as an alkyl group wherein ahydrogen has been replaced by an alkoxy group. The term“(alkylthio)alkyl” is defined similarly as alkoxyalkyl, except a sulfuratom, rather than an oxygen atom, is present.

[0056] The term “hydroxyalkyl” is defined as a hydroxy group appended toan alkyl group.

[0057] The term “amino” is defined as —NH₂, and the term “alkylamino” isdefined as —NR₂, wherein at least one R is alkyl and the second R isalkyl or hydrogen.

[0058] The term “acylamino” is defined as RC(═O)N, wherein R is alkyl oraryl.

[0059] The term “alkylthio” is defined as —SR, wherein R is alkyl.

[0060] The term “alkylsulfinyl” is defined as R—SO₂, wherein R is alkyl.

[0061] The term “alkylsulfonyl” is defined as R—SO₃, wherein R is alkyl.

[0062] The term “nitro” is defined as —NO₂.

[0063] The term “trifluoromethyl” is defined as —CF₃.

[0064] The term “trifluoromethoxy” is defined as —OCF₃.

[0065] The term “spiro” as used herein refers to a group having twocarbon atoms directly bonded to the carbon atom to which R¹ is attached.

[0066] The term “cyano” is defined as —CN.

[0067] In a preferred embodiment, q is 0. In other preferredembodiments, R⁰ is selected from the group consisting of C₁₋₆alkyl,aryl, heteroaryl, Het, OR^(a), C(═O)OR^(a), C₁₋₄alkyleneNR^(a)R^(b),OC(═O)R^(a), C(═O)R^(a), NR^(a)R^(b), C₃₋₈cycloalkyl, C₃₋₈cycloalkylQ,C(═O)NR^(a)R^(b), and C(═O)NR^(b)R^(c).

[0068] In a preferred group of compounds of formula (I), R¹ isrepresented by

[0069] wherein the bicyclic ring can represent, for example, naphthaleneor indene, or a heterocycle, such as benzoxazole, benzothiazole,benzisoxazole, benzimidazole, quinoline, indole, benzothiophene, orbenzofuran, or

[0070] wherein m is an integer 1 or 2, and G, independently, isC(R^(a))₂, O, S, or NR^(a). The bicyclic ring comprising the R¹substituent typically is attached to the rest of the molecule by aphenyl ring carbon atom.

[0071] In a more preferred group of compounds of formula (I), R¹ isrepresented by an optionally substituted bicyclic ring

[0072] wherein m is 1 or 2, and G, independently, are C(R^(a))₂ or O.Especially preferred R¹ substituents include

[0073] Within this particular group of compounds, nonlimiting examplesof substituents for the aromatic ring include halogen (e.g., chlorine),C₁₋₃alkyl (e.g., methyl, ethyl, or i-propyl), OR^(a) (e.g., methoxy,ethoxy, or hydroxy), CO₂R^(a), halomethyl or halomethoxy (e.g.,trifluoromethyl or trifluoromethoxy), cyano, NR^(a)C(═O)R^(a), nitro,and NR^(a)R^(b).

[0074] In other preferred embodiments, R¹ is optionally substituted andselected from the group consisting of C₁₋₄alkyleneQR^(a),C₁₋₄alkyleneQC₁₋₄alkyleneQR^(a), C₃₋₈cycloalkyl, C₃₋₈cycloalkenyl,C₁₋₆alkyl,

[0075] In a more preferred group of compounds of formula (I), R¹ isrepresented by

[0076] C₃₋₈cycloalkyl, C₃₋₈cycloalkenyl, C₁₋₆alkyl, C₁₋₄alkyleneQR^(a),and C₁₋₄alkyleneQC₁₋₄alkyleneQR^(a). A preferred Q is oxygen.

[0077] Some preferred R¹ substituents are

[0078] Within this particular group of compounds, preferred R^(a)substituents include hydrogen, C₁₋₆alkyl, and benzyl.

[0079] In a preferred embodiment, R² is selected from the groupconsisting of hydrogen, aryl, heteroaryl, OR^(a), NR^(a)R^(b),NR^(b)R^(c), C₁₋₄alkyleneHet, C₁₋₄alkyleneheteroaryl, C₁₋₄alkylenearyl,C₁₋₄alkyleneC(═O)C₁₋₄-alkylenearyl, C₁₋₄alkyleneC(═O)OR^(a),C₁₋₄alkyleneC(═O)—NR^(b)R^(c), C₁₋₄alkyleneC(═O)Het,C₁₋₄alkyleneNR^(b)R^(c), C₁₋₄-alkyleneNR^(a)C(═O)R^(a), andC₁₋₄alkyleneOC₁₋₄alkyleneOR^(a).

[0080] In a more preferred embodiment, R² is hydrogen.

[0081] In preferred embodiments, R³ is hydrogen, C₁₋₆alkyl, aryl, orheteroaryl.

[0082] In preferred embodiments, Y is null, or is C(═O), C(═O)C≡C,C(═O)(CH₂)_(t), SO₂, or C(═S).

[0083] In preferred embodiments, A is selected from the group consistingof

[0084] R⁴ is selected from the group consisting of hydrogen, C₁₋₆alkyl,aryl, heteroaryl, halo, C(═O)OR^(b), NHC(═O)C₁₋₃alkyleneN(R^(b))₂, NO₂,C(═O)OR^(b), OR^(b), CF₃, OR^(a), CN, OC(═O)R^(b), arylOR^(b), Het,NR^(a)C(═O)C₁₋₃alkyleneC(═O)—OR^(a), arylOC₁₋₃alkyleneNR^(a)R^(b),arylOC(═O)R^(a), C₁₋₄alkylene-C(═O)OR^(b), OC₁₋₄alkyleneC(═O)OR^(b),C(═O)NR^(b)SO₂R^(c), C₁₋₄-alkyleneNR^(b)R^(c),C₂₋₆alkenyleneNR^(b)R^(c), C(═O)NR^(b)C₁₋₄alkyleneOR^(b),NR^(b)C₁₋₄alkyleneNR^(b)R^(c), NR^(b)C(═O)R^(c), NR^(b)C(═O)NR^(b)R^(c),OSO₂CF₃, C(═O)R^(b), C₁₋₃alkylenearyl, C₁₋₄alkyleneHet,C₁₋₆alkyleneOR^(b), C₁₋₃alkyleneN(R^(b))₂, NR^(b)R^(c),C(═O)NR^(b)R^(c), NHC(═O)C₁-C₃alkylenearyl, C₃₋₈cycloalkyl,C₃₋₈hetero-cycloalkyl, NHC(═O)C₁₋₃alkyleneHet, NHC(═O)haloC₁₋₆-alkyl,and

[0085] In preferred embodiments, p is 0 or R⁵ groups, independently, areselected from the group consisting of halo, oxo, C₁₋₆alkyl, NR^(a)R^(b),or OR^(a).

[0086] In especially preferred embodiments, q is 0 or R⁰ is selectedfrom the group consisting of halo, methyl, trifluoromethyl, andtrifluoromethoxy; R¹ is selected from the group consisting of

[0087] R² is selected from the group consisting of hydrogen, C₁₋₆alkyl,C(═O)NR^(b)R^(c), and C₁₋₄alkyleneHet; R³ is selected from the groupconsisting of hydrogen, C₁₋₆alkyl, aryl, and heteroaryl; Y is null, or Yis selected from the group consisting of selected from the groupconsisting of C(═O), C(═O)C≡C, C(═O)CH₂, C(═O)CH₂CH₂, and SO₂; A isselected from the group consisting of

[0088] R⁴ is selected from the group consisting of H, NHC(═O)CH₃,N(CH₃)₂, C(═O)NH₂, NHCH₃, NO₂, NH₂, Br, C(═O)CH₃, OCH₃, CH₂OCH₃,NHC(═O)CH₂N(CH₃)₂, CH₂N(CH₃)₂, CH₃, Cl, NHC(═O)CH₂CO₂H,

[0089] p is 0 or R⁵ groups, independently, are selected from the groupconsisting of CH₃, Cl, oxo, and OCH₃.

[0090] An especially preferred subclass of compounds within the generalscope of formula (I) is represented by compounds of formula (III)

[0091] and pharmaceutically acceptable salts and solvates (e.g.,hydrates) thereof.

[0092] Compounds of formula (I) can contain one or more asymmetriccenter, and, therefore, can exist as stereoisomers. The presentinvention includes both mixtures and separate individual stereoisomersof the compounds of formula (I). Compounds of formula (I) also can existin tautomeric forms, and the invention includes both mixtures andseparate individual tautomers thereof.

[0093] Pharmaceutically acceptable salts of the compounds of formula (I)can be acid addition salts formed with pharmaceutically acceptableacids. Examples of suitable salts include, but are not limited to, thehydrochloride, hydrobromide, sulfate, bisulfate, phosphate, hydrogenphosphate, acetate, benzoate, succinate, fumarate, maleate, lactate,citrate, tartrate, gluconate, methanesulfonate, benzenesulfonate, andp-toluenesulfonate salts. The compounds of formula (I) also can providepharmaceutically acceptable metal salts, in particular alkali metalsalts and alkaline earth metal salts, with bases. Examples include thesodium, potassium, magnesium, and calcium salts.

[0094] Compounds of the present invention are potent and selectiveinhibitors of cGMP-specific PDE5. Thus, compounds of formula (I) are ofinterest for use in therapy, specifically for the treatment of a varietyof conditions where selective inhibition of PDE5 is considered to bebeneficial.

[0095] Phosphodiesterases (PDEs) catalyze the hydrolysis of cyclicnucleotides, such as cyclic adenosine monophosphate (cAMP) and cyclicguanosine monophosphate (cGMP). The PDEs have been classified into atleast seven isoenzyme families and are present in many tissues (J. A.Beavo, Physiol. Rev., 75, p. 725 (1995)).

[0096] PDE5 inhibition is a particularly attractive target. A potent andselective inhibitor of PDE5 provides vasodilating, relaxing, anddiuretic effects, all of which are beneficial in the treatment ofvarious disease states. Research in this area has led to several classesof inhibitors based on the cGMP basic structure (E. Sybertz et al.,Expert. Opin. Ther. Pat., 7, p. 631 (1997)).

[0097] The biochemical, physiological, and clinical effects of PDE5inhibitors therefore suggest their utility in a variety of diseasestates in which modulation of smooth muscle, renal, hemostatic,inflammatory, and/or endocrine function is desirable. The compounds offormula (I), therefore, have utility in the treatment of a number ofdisorders, including stable, unstable, and variant (Prinzmetal) angina,hypertension, pulmonary hypertension, congestive heart failure, acuterespiratory distress syndrome, acute and chronic renal failure,atherosclerosis, conditions of reduced blood vessel patency (e.g.,postpercutaneous transluminal coronary or carotid angioplasty, orpost-bypass surgery graft stenosis), peripheral vascular disease,vascular disorders, such as Raynaud's disease, thrombocythemia,inflammatory diseases, stroke, bronchitis, chronic asthma, allergicasthma, allergic rhinitis, glaucoma, osteoporosis, preterm labor, benignprostatic hypertrophy, peptic ulcer, male erectile dysfunction, femalesexual dysfunction, and diseases characterized by disorders of gutmotility (e.g., irritable bowel syndrome).

[0098] An especially important use is the treatment of male erectiledysfunction, which is one form of impotence and is a common medicalproblem. Impotence can be defined as a lack of power, in the male, tocopulate, and can involve an inability to achieve penile erection orejaculation, or both. The incidence of erectile dysfunction increaseswith age, with about 50% of men over the age of 40 suffering from somedegree of erectile dysfunction.

[0099] In addition, a further important use is the treatment of femalearousal disorder. Female arousal disorders are defined as a recurrentinability to attain or maintain an adequate lubrication/swellingresponse of sexual excitement until completion of sexual activity. Thearousal response consists of vasocongestion in the pelvis, vaginallubrication, and expansion and swelling of external genitalia.

[0100] It is envisioned, therefore, that compounds of formula (I) areuseful in the treatment of male erectile dysfunction and female arousaldisorder. Thus, the present invention concerns the use of compounds offormula (I), or a pharmaceutically acceptable salt thereof, or apharmaceutical composition containing either entity, for the manufactureof a medicament for the curative or prophylactic treatment of erectiledysfunction in a male animal and arousal disorder in a female animal,including humans.

[0101] The term “treatment” includes preventing, lowering, stopping, orreversing the progression or severity of the condition or symptoms beingtreated. As such, the term “treatment” includes both medical therapeuticand/or prophylactic administration, as appropriate.

[0102] It also is understood that “a compound of formula (I),” or aphysiologically acceptable salt or solvate thereof, can be administeredas the neat compound, or as a pharmaceutical composition containingeither entity.

[0103] Although the compounds of the invention are envisioned primarilyfor the treatment of sexual dysfunction in humans, such as male erectiledysfunction and female arousal disorder, they also can be used for thetreatment of other disease states.

[0104] A further aspect of the present invention, therefore, isproviding a compound of formula (I) for use in the treatment of stable,unstable, and variant (Prinzmetal) angina, hypertension, pulmonaryhypertension, chronic obstructive pulmonary disease, congestive heartfailure, acute respiratory distress syndrome, acute and chronic renalfailure, atherosclerosis, conditions of reduced blood vessel patency(e.g., post-PTCA or post-bypass graft stenosis), peripheral vasculardisease, vascular disorders such as Raynaud's disease, thrombocythemia,inflammatory diseases, prophylaxis of myocardial infarction, prophylaxisof stroke, stroke, bronchitis, chronic asthma, allergic asthma, allergicrhinitis, glaucoma, osteoporosis, preterm labor, benign prostatichypertrophy, male and female erectile dysfunction, or diseasescharacterized by disorders of gut motility (e.g., IBS).

[0105] According to another aspect of the present invention, there isprovided the use of a compound of formula (I) for the manufacture of amedicament for the treatment of the above-noted conditions anddisorders.

[0106] In a further aspect, the present invention provides a method oftreating the above-noted conditions and disorders in a human or nonhumananimal body which comprises administering to said body a therapeuticallyeffective amount of a compound of formula (I).

[0107] Compounds of the invention can be administered by any suitableroute, for example by oral, buccal, inhalation, sublingual, rectal,vaginal, transurethral, nasal, topical, percutaneous, i.e., transdermal,or parenteral (including intravenous, intramuscular, subcutaneous, andintracoronary) administration. Parenteral administration can beaccomplished using a needle and syringe, or using a high pressuretechnique, like POWDERJECT™.

[0108] Oral administration of a compound of the invention is thepreferred route. Oral administration is the most convenient and avoidsthe disadvantages associated with other routes of administration. Forpatients suffering from a swallowing disorder or from impairment of drugabsorption after oral administration, the drug can be administeredparenterally, e.g., sublingually or buccally.

[0109] Compounds and pharmaceutical compositions suitable for use in thepresent invention include those wherein the active ingredient isadministered in an effective amount to achieve its intended purpose.More specifically, a “therapeutically effective amount” means an amounteffective to prevent development of, or to alleviate the existingsymptoms of, the subject being treated. Determination of the effectiveamounts is well within the capability of those skilled in the art,especially in light of the detailed disclosure provided herein.

[0110] A “therapeutically effective dose” refers to that amount of thecompound that results in achieving the desired effect. Toxicity andtherapeutic efficacy of such compounds can be determined by standardpharmaceutical procedures in cell cultures or experimental animals,e.g., for determining the LD₅₀ (the dose lethal to 50% of thepopulation) and the ED₅₀ (the dose therapeutically effective in 50% ofthe population). The dose ratio between toxic and therapeutic effects isthe therapeutic index, which is expressed as the ratio between LD₅₀ andED₅₀. Compounds which exhibit high therapeutic indices are preferred.The data obtained from such data can be used in formulating a range ofdosage for use in humans. The dosage of such compounds preferably lieswithin a range of circulating concentrations that include the ED₅₀ withlittle or no toxicity. The dosage can vary within this range dependingupon the dosage form employed, and the route of administration utilized.

[0111] The exact formulation, route of administration, and dosage can bechosen by the individual physician in view of the patient's condition.Dosage amount and interval can be adjusted individually to provideplasma levels of the active moiety which are sufficient to maintain thetherapeutic effects.

[0112] The amount of composition administered is dependent on thesubject being treated, on the subject's weight, the severity of theaffliction, the manner of administration, and the judgment of theprescribing physician.

[0113] Specifically, for administration to a human in the curative orprophylactic treatment of the conditions and disorders identified above,oral dosages of a compound of formula (I) generally are about 0.5 toabout 1000 mg daily for an average adult patient (70 kg). Thus, for atypical adult patient, individual tablets or capsules contain 0.2 to 500mg of active compound, in a suitable pharmaceutically acceptable vehicleor carrier, for administration in single or multiple doses, once orseveral times per day. Dosages for intravenous, buccal, or sublingualadministration typically are 0.1 to 500 mg per single dose as required.In practice, the physician determines the actual dosing regimen which ismost suitable for an individual patient, and the dosage varies with theage, weight, and response of the particular patient. The above dosagesare exemplary of the average case, but there can be individual instancesin which higher or lower dosages are merited, and such are within thescope of this invention.

[0114] For human use, a compound of the formula (I) can be administeredalone, but generally is administered in admixture with a pharmaceuticalcarrier selected with regard to the intended route of administration andstandard pharmaceutical practice. Pharmaceutical compositions for use inaccordance with the present invention thus can be formulated in aconventional manner using one or more physiologically acceptablecarriers comprising excipients and auxiliaries that facilitateprocessing of compounds of formula (I) into preparations which can beused pharmaceutically.

[0115] These pharmaceutical compositions can be manufactured in aconventional manner, e.g., by conventional mixing, dissolving,granulating, dragee-making, levigating, emulsifying, encapsulating,entrapping, or lyophilizing processes. Proper formulation is dependentupon the route of administration chosen. When a therapeuticallyeffective amount of a compound of the present invention is administeredorally, the composition typically is in the form of a tablet, capsule,powder, solution, or elixir. When administered in tablet form, thecomposition can additionally contain a solid carrier, such as a gelatinor an adjuvant. The tablet, capsule, and powder contain about 5% toabout 95% compound of the present invention, and preferably from about25% to about 90% compound of the present invention. When administered inliquid form, a liquid carrier such as water, petroleum, or oils ofanimal or plant origin can be added. The liquid form of the compositioncan further contain physiological saline solution, dextrose or othersaccharide solutions, or glycols. When administered in liquid form, thecomposition contains about 0.5% to about 90% by weight of a compound ofthe present invention, and preferably about 1% to about 50% of acompound of the present invention.

[0116] When a therapeutically effective amount of a compound of thepresent invention is administered by intravenous, cutaneous, orsubcutaneous injection, the composition is in the form of apyrogen-free, parenterally acceptable aqueous solution. The preparationof such parenterally acceptable solutions, having due regard to pH,isotonicity, stability, and the like, is within the skill in the art. Apreferred composition for intravenous, cutaneous, or subcutaneousinjection typically contains, in addition to a compound of the presentinvention, an isotonic vehicle.

[0117] For oral administration, the compounds can be formulated readilyby combining a compound of formula (I) with pharmaceutically acceptablecarriers well known in the art. Such carriers enable the presentcompounds to be formulated as tablets, pills, dragees, capsules,liquids, gels, syrups, slurries, suspensions and the like, for oralingestion by a patient to be treated. Pharmaceutical preparations fororal use can be obtained by adding a compound of formula (I) with asolid excipient, optionally grinding a resulting mixture, and processingthe mixture of granules, after adding suitable auxiliaries, if desired,to obtain tablets or dragee cores. Suitable excipients include, forexample, fillers and cellulose preparations. If desired, disintegratingagents can be added.

[0118] For administration by inhalation, compounds of the presentinvention are conveniently delivered in the form of an aerosol spraypresentation from pressurized packs or a nebulizer, with the use of asuitable propellant. In the case of a pressurized aerosol, the dosageunit can be determined by providing a valve to deliver a metered amount.Capsules and cartridges of, e.g., gelatin, for use in an inhaler orinsufflator can be formulated containing a powder mix of the compoundand a suitable powder base such as lactose or starch.

[0119] The compounds can be formulated for parenteral administration byinjection, e.g., by bolus injection or continuous infusion. Formulationsfor injection can be presented in unit dosage form, e.g., in ampules orin multidose containers, with an added preservative. The compositionscan take such forms as suspensions, solutions, or emulsions in oily oraqueous vehicles, and can contain formulatory agents such as suspending,stabilizing, and/or dispersing agents.

[0120] Pharmaceutical formulations for parenteral administration includeaqueous solutions of the active compounds in water-soluble form.Additionally, suspensions of the active compounds can be prepared asappropriate oily injection suspensions. Suitable lipophilic solvents orvehicles include fatty oils or synthetic fatty acid esters. Aqueousinjection suspensions can contain substances which increase theviscosity of the suspension. Optionally, the suspension also can containsuitable stabilizers or agents that increase the solubility of thecompounds and allow for the preparation of highly concentratedsolutions. Alternatively, a present composition can be in powder formfor constitution with a suitable vehicle, e.g., sterile pyrogen-freewater, before use.

[0121] Compounds of the present invention also can be formulated inrectal compositions, such as suppositories or retention enemas, e.g.,containing conventional suppository bases. In addition to theformulations described previously, the compounds also can be formulatedas a depot preparation. Such long-acting formulations can beadministered by implantation (for example, subcutaneously orintramuscularly) or by intramuscular injection. Thus, for example, thecompounds can be formulated with suitable polymeric or hydrophobicmaterials (for example, as an emulsion in an acceptable oil) or ionexchange resins, or as sparingly soluble derivatives, for example, as asparingly soluble salt.

[0122] Many of the compounds of the present invention can be provided assalts with pharmaceutically compatible counterions. Suchpharmaceutically acceptable base addition salts are those salts thatretain the biological effectiveness and properties of the free acids,and that are obtained by reaction with suitable inorganic or organicbases.

[0123] In particular, a compound of formula (I) can be administeredorally, buccally, or sublingually in the form of tablets containingexcipients, such as starch or lactose, or in capsules or ovules, eitheralone or in admixture with excipients, or in the form of elixirs orsuspensions containing flavoring or coloring agents. Such liquidpreparations can be prepared with pharmaceutically acceptable additives,such as suspending agents. A compound also can be injected parenterally,for example, intravenously, intramuscularly, subcutaneously, orintracoronarily. For parenteral administration, the compound is bestused in the form of a sterile aqueous solution which can contain othersubstances, for example, salts, or monosaccharides, such as mannitol orglucose, to make the solution isotonic with blood.

[0124] For veterinary use, a compound of formula (I) or a nontoxic saltthereof, is administered as a suitably acceptable formulation inaccordance with normal veterinary practice. The veterinarian can readilydetermine the dosing regimen and route of administration that is mostappropriate for a particular animal.

[0125] Thus, the invention provides in a further aspect a pharmaceuticalcomposition comprising a compound of the formula (I), together with apharmaceutically acceptable diluent or carrier therefor. There isfurther provided by the present invention a process of preparing apharmaceutical composition comprising a compound of formula (I), whichprocess comprises mixing a compound of formula (I), together with apharmaceutically acceptable diluent or carrier therefor.

[0126] In a particular embodiment, the invention includes apharmaceutical composition for the curative or prophylactic treatment oferectile dysfunction in a male animal, or arousal disorder in a femaleanimal, including humans, comprising a compound of formula (I) or apharmaceutically acceptable able salt thereof, together with apharmaceutically acceptable diluent or carrier.

[0127] Compounds of formula (I) can be prepared by any suitable methodknown in the art, or by the following processes which form part of thepresent invention. In the methods below, R⁰, R¹, R², R³, R⁴, and R⁵, aswell as Y and A, are defined as in structural formula (I) above. Forexample, compounds of structural formula (I) can be prepared accordingto the following synthetic scheme, which comprises reacting compounds offormulae (IV) and (V). This type of reaction is described in BombrunU.S. Pat. No. 6,117,881, incorporated herein by reference.

[0128] The reaction is performed in the presence of1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) and1-hydroxybenzotriazole (HOBT) in a suitable organic solvent, such asdimethylformamide (DMF) or dichloromethane (CH₂Cl₂) for several hours,e.g., 8 hours to 2 days.

[0129] A compound of formula (IV) can be prepared by Pictet-Spenglercyclization between a tryptamine derivative of formula (VI) and analdehyde of formula R¹CHO.

[0130] The reaction can be performed in a suitable solvent such as ahalogenated hydrocarbon (e.g., dichloromethane) or an aromatichydrocarbon (e.g., toluene) in the presence of an acid, such astrifluoroacetic acid (TFA). The reaction can be performed at atemperature of 20° C. to reflux to provide a compound of formula (IV) inone step. The reaction also can be carried out in a solvent, such as anaromatic hydrocarbon (e.g., toluene), under reflux, optionally using aDean-Stark apparatus to trap the produced water.

[0131] The reaction provides racemic compounds of formula (IV).Enantiomers can be obtained from a resolution of N-acetyl leucine usingfractional crystallization in EtOAc:MeOH (ethyl acetate:methanol) as thesolvent. (R) and (S) enantiomers can be isolated as salts, dependingupon whether N-acetyl-(D)- and -(L)-leucine was used as the startingmaterial.

[0132] Compounds of formulae (VI) and R¹CHO are commercially availablecompounds or are prepared by standard synthetic techniques.

[0133] The following examples show other synthetic methods for thepreparation of compounds of structural formula (I).

[0134] It should be understood that protecting groups can be utilized inaccordance with general principles of synthetic organic chemistry toprovide compounds of structural formula (I). Protecting group-formingreagents, like benzyl chloroformate and trichloroethyl chloroformate,are well known to persons skilled in the art, for example, see T. W.Greene et al., “Protective Groups in Organic Synthesis, Third Edition,”John Wiley and Sons, Inc., NY, N.Y. (1999). These protecting groups areremoved when necessary by appropriate basic, acidic, or hydrogenolyticconditions known to persons skilled in the art. Accordingly, compoundsof structural formula (I) not specifically exemplified herein can beprepared by persons skilled in the art.

[0135] In addition, compounds of formula (I) can be converted to othercompounds of formula (I). Thus, for example, a particular R substituentcan be interconverted to prepare another suitably substituted compoundof formula (I). Examples of appropriate interconversions include, butare not limited to, OR^(a) to hydroxy by suitable means (e.g., using anagent such as BBr₃ or a palladium catalyst, like palladium-on-carbon,with hydrogen), or amino to substituted amino, such as acylamino orsulphonylamino, using standard acylating or sulfonylating conditions.

[0136] Compounds of formula (I) can be prepared by the method above asindividual stereoisomers or as a racemic mixture. Individualstereoisomers of the compounds of the invention can be prepared fromracemates by resolution using methods known in the art for theseparation of racemic mixtures into their constituent stereoisomers, forexample, using HPLC on a chiral column, such as Hypersil naphthyl urea,or using separation of salts of stereoisomers. Compounds of theinvention can be isolated in association with solvent molecules bycrystallization, from, or evaporation of, an appropriate solvent.

[0137] The pharmaceutically acceptable acid addition salts of thecompounds of formula (I) that contain a basic center can be prepared ina conventional manner. For example, a solution of the free base can betreated with a suitable acid, either neat or in a suitable solution, andthe resulting salt isolated either by filtration or by evaporation undervacuum of the reaction solvent. Pharmaceutically acceptable baseaddition salts can be obtained in an analogous manner by treating asolution of a compound of formula (I) with a suitable base. Both typesof salt can be formed or interconverted using ion-exchange resintechniques. Thus, according to a further aspect of the invention, amethod for preparing a compound of formula (I) or a salt or solvate(e.g., hydrate) is provided, followed by (i) salt formation, or (ii)solvate (e.g., hydrate) formation.

[0138] The following additional abbreviations are used hereafter in theaccompanying examples: rt (room temperature), min (minute), h (hour), g(gram), mmol (millimole), m.p. (melting point), eq (equivalents), L(liter), mL (milliliter), μL (microliter), saturated (sat.), DMSO(dimethyl sulfoxide), CH₂Cl₂ (dichloromethane), IPA (isopropyl alcohol),TFA (trifluoroacetic acid), EtOH (ethanol), MeOH (methanol), DMF(dimethylformamide), CHCl₃ (chloroform), NaOH (sodium hydroxide), Na₂SO₄(sodium sulfate), Et₂O (diethyl ether), EtOAc (ethyl acetate), Na₂CO₃(sodium carbonate), MgSO₄ (magnesium sulfate), iPr₂O (diisopropylether), NaHCO₃ (sodium bicarbonate), Et₃N (triethylamine), AcOH (aceticacid), and THF (tetrahydrofuran).

[0139] Intermediate 1

1-Phenyl-2,3,4,9-tetrahydro-1H-β-carboline

[0140]

[0141] A solution of tryptamine (15 g, 94.0 mmol) and benzaldehyde (10.9g, 1.1 eq.) in CH₂Cl₂ (800 mL) was treated with TFA (15 mL, 2 eq.). Theresulting mixture was stirred at room temperature (rt) for one day, thenneutralized to pH 7 with a saturated aqueous solution of Na₂CO₃. Afterfiltration and concentration to dryness, the residue was recrystallizedfrom IPA to give Intermediate 1 (11.0 9, 47%) as white crystals(m.p.:175-177° C.).

[0142] Intermediate 2

1-(3,4-Methylenedioxyphenyl)-2,3,4,9-tetrahydro-1H-β-carboline

[0143]

[0144] Intermediate 2 was prepared by the same procedure as Intermediate1 using tryptamine (20.0 g, 120 mmol), 3,4-methylenedioxybenzaldehyde(20.6 g, 1.1 eg.) and TFA (18 mL, 2 eq.) to give Intermediate 2 (22 g,60%) as white crystals after recryslatllizatoin from ethanol (m.p.:178°C.).

[0145] Intermediate 3

1-(2,3-Dihydrobenzofuran-5-yl)-2,3,4,9-tetrahydro-1H-β-carboline

[0146]

[0147] Intermediate 3 was prepared using a two-step procedure. Asolution of tryptamine (32.4 g, 0.2 mol) and2,3-dihydrobenzofuran-5-carboxaldehyde (30.0 g, 1 eq.) in toluene (1 L)was heated under reflux for 4 hours. After removal of 4 mL of water andevaporation of toluene, the residue was dissolved in CH₂Cl₂ (1 L) in thepresence of TFA (31 mL, 2 eq.). The resulting mixture was stirred at rtfor 16 hours. Then, 1 L of a saturated aqueous solution of NaHCO₃ wasadded. After extraction with CH₂Cl₂ and drying over MgSO₄, the organicsolution was evaporated in vacuo. Recrystallization from CH₂Cl₂/−iPr₂O(2:30) gave the title compound as white crystals in an 80% yield. ¹H NMR(CDCl₃), δ 7.6 (s, 1H), 7.5-7.6 (m, 1H), 7-7.3 (m, 5H), 6.7-6.75 (d,1H), 5.1 (s, 1H), 4.5-4.6 (t, 2H), 3.3-3.45 (m, 1H), 3.05-3.2 (t, 3H),2.7-3 (m, 2H).

[0148] Intermediate 4

(R)-1-(2,3-Dihydrobenzofuran-5-yl)-2,3,4,9-tetrahydro-1H-β-carboline

[0149] Resolution of the racemic Intermediate 3 was achieved usingN-acetyl-(D)-leucine (Sigma) in MeOH:EtOAc followed by recrystallizationfrom MeOH. The suspension of the recrystallized material in CH₂Cl₂ wastreated with a sat. aqueous NaHCO₃ to give the enantiomerically pureIntermediate 4 in 55%

[0150] yield (m.p.:98-99° C.). Analysis for C₁₉H₁₈N₂O.0.15 H₂O:Calculated: C, 77.87; H, 6.29; N, 9.56. Found: C, 77.83; H, 6.33; N,9.44. [α]_(D) ²¹=+42° (c=0.5, MeOH).

[0151] Intermediates 5 and 6 were prepared from Intermediate 2 and theappropriate carboxylic acid or acid chloride. Intermediate 7 wasprepared from benzylamine and terephthalic acid.

[0152] Intermediate 5

(E)-1-(1-Benzo[1,3]dioxol-5-yl-1,3,4,9-tetrahydro-β-carbolin-2-yl)-3-(2-nitrophenyl)propenone

[0153]

[0154] Intermediate 6

4-[1-(1-Benzo[1,3]dioxol-5-yl-1,3,4,9-tetrahydro-β-carbolin-2-yl)methanolyl]benzoicacid methyl ester

[0155]

[0156] Intermediate 7

N-Benzylterephthalamic acid

[0157]

EXAMPLE 11-(2H-Benzo[d]1,3-dioxolan-5-yl)(1,2,3,4-tetrahydro-β-carbolin-2-yl)-2-naphthylketone

[0158]

[0159] Naphthalene-2-carbonyl chloride was added to Intermediate 2 toprovide Example 1 in 75% yield: mp 248-249° C. ¹H NMR (DMSO-d₆) δ: 11.1(s, 0.2H), 11.08 (s, 0.8H), 8.06-7.95 (m, 2H), 7.74-7.24 (m, 7H),7.15-6.76 (m, 6H), 6.15 (s, 2H), 3.47-3.17 (m, 2H), 2.85-2.40 (m, 2H);MS ES+m/e 447 (p+1), ES−m/e 445 (m−1) ; IR (KBr, cm¹): 3282, 1617, 1633.

EXAMPLE 21-(2H-benzo[d]1,3-dioxolan-5-yl)(1R)(1,2,3,4-tetrahydro-β-carbolin-2-yl)2-naphthylketone

[0160]

[0161] Naphthalene-2-carbonyl chloride was added to the (1R)stereoisomer of Intermediate 2 to provide Example 2 in 74% yield. mp285° C. ¹H NMR (DMSO-d₆) δ: 11.1 (s, 0.2H), 11.08 (s, 0.8H), 8.06-7.95(m, 2H), 7.74-7.24 (m, 7H), 7.15-6.76 (m, 6H), 6.15 (s, 2H), 3.47-3.17(m, 2H), 2.85-2.40 (m, 2H); MS ES+m/e 447 (p+1), ES−m/e 445 (p−1); IR(KBr, cm⁻¹): 3282, 1617, 1633; 100% ee.

EXAMPLE 31-(1-Benzo[1,3]dioxol-5-yl-1,3,4,9-tetrahydro-β-carbolin-2-yl)-1-Phenylmethane

[0162]

[0163] Intermediate 2 (0.68 mole, 200 mg) was reacted with benzoylchloride (1.5 eq.) and NaHCO₃ (1.1 eq.) in CH₂Cl₂ by stirring thereaction mixture at room temperature. The reaction was quenched withaqueous sat. NaHCO₃. The resulting mixture was extracted with CH₂Cl₂,and the organic phase was dried. After filtering and removing thesolvent by evaporation, Example 3 was purified by flash chromatography,eluting with CH₂Cl₂. The product was recrystallizated from EtOH/CH₂Cl₂(3/1) to provide Example 3 as white crystals. (m.p. 260-261° C.), m.w.396.45 (C₂₅H₂₀N₂O₃).

EXAMPLE 4N-{4[1-(1-Benzo[1,3]dioxol-5-yl-1,3,4,9-tetrahydro-β-carboline-2-yl)-methanoyl]phenyl}acetamide

[0164]

[0165] Intermediate 2 was reacted with 4-acetamidobenzoic acid in CH₂Cl₂in the presence of EDCI and Et₃N. The reaction product was isolated andpurified by flash chromatography, eluting with CH₂Cl₂/MeOH (98:2).Recrystallization from ethanol yielded Example 4 as a white solid. m.p.186-188° C., m.w. 453.5 (C₂₇H₂₃N₃O₄).

EXAMPLE 51-(1-Benzo[1,3]dioxol-5-yl-1,3,4,9-tetrahydro-β-carbolin-2-yl)-1-(4-methylaminophenyl)methanone

[0166]

[0167] Intermediate 2 was reacted with 4-(methylamino)benzoic acid inCH₂Cl₂ in the presence of EDCI and Et₃N. The reaction product wasisolated and purified. Recrystallization yielded Example 5 as a whitesolid. m.w. 425.45 (C₂₆H₂₃N₃O₃).

EXAMPLE 61-(1-Benzo[1,3]dioxol-5-yl-1,3,4,9-tetrahydro-β-carbolin-2-yl)-1-(4-dimethylaminophenyl)methanone

[0168]

[0169] Intermediate 2 was reacted with 4-(dimethylamino)benzoic acid inCH₂Cl₂ in the presence of EDCI and Et₃N. The reaction product wasisolated and purified. Recrystallization from CH₂Cl₂ yielded Example 6as a white solid. m.w. 439.12 (C₂₇H₂₅N₃O₃).

EXAMPLE 74-[1-(1-Benzo[1,3]dioxol-5-yl-1,3,4,9-tetrahydro-β-carbolin-2-yl)methanoyl]benzamide

[0170]

[0171] Intermediate 6 was dissolved in 100 mL of CH₃0H, then reactedwith ammonia at 35° C. for about 2 hours. The CH₃OH was evaporated, andthe residue was extracted with CH₂Cl₂, followed by washing with brine.After drying, the CH₂Cl₂ was removed to yield Example 7. m.w. 439.47(C₂₆H₂₁N₃O₄).

EXAMPLE 81-(1-Benzo[1,3]dioxol-5-yl-1,3,4,9-tetrahydro-β-carbolin-2-yl)-3-phenylpropynone

[0172]

[0173] Intermediate 2 was reacted with 3-phenylpropyne carboxylic acidin CH₂Cl₂ in the presence of HOBT, EDCI, and Et₃N. The reaction productwas isolated and purified by flash chromatography, eluting with CH₂Cl₃.Recrystallization from EtOH yielded Example 8 as a white solid. m.p.145.6° C., m.w. 420.47 (C₂₇H₂₀N₂O₃).

EXAMPLE 9

[0174]3-(2-Aminophenyl)-1-(1-benzo[1,3]dioxol-5-yl-1,3,4,9-tetrahydro-β-carbolin-2-yl)propan-1-one

[0175] Intermediate 5 was hydrogenated in the presence of a Pd/C(palladium on carbon) catalyst in a 50/50 mixture of EtOH/THF. Thereaction was allowed to proceed for four hours, followed by filtering ofthe Pd/C catalyst from the reaction mixture, and removing the solventsby evaporation. The resulting product was extracted with CH₂Cl₂, whichthen was removed by evaporation. The reaction product was purified bychromatography, eluting with CH₂Cl₂. The product was recrystallized froma water/IPA solution to yield Example 9 as a white solid. (m.p. 214°C.), m.w. 439.52 (C₂₇H₂₅N₃O₃).

EXAMPLE 10N-{4-[1-(1-Benzo[1,3]dioxol-5-yl-1,3,4,9-tetrahydro-β-carbolin-2-yl)methanoyl]phenyl}-2-phenylacetamide

[0176]

[0177] Intermediate 2 was reacted with Intermediate 7 in CH₂Cl₂ in thepresence of HOBT, EDCI, and Et₃N. The reaction product was isolated andpurified by flash chromatography, eluting with CH₂Cl₂/MeOH (95:5).Recrystallization from EtOH/−water yielded Example 10 as a white solid.(m.p. 151-152° C.), m.w. 529.60 (C₃₃H₂₇N₃O₄).

EXAMPLE 111-(1-Benzo[1,3]dioxol-5-yl-1,3,4,9-tetrahydro-β-carbolin-2-yl)-3-phenylpropan-1-one

[0178]

[0179] Intermediate 2 was reacted with 3-phenylpropanoic acid in CH₂Cl₂in the presence of EDCI, HOBT, and Et₃N. The reaction product wasisolated and purified. Recrystallization from CH₃OH yielded Example 11as a white solid. m.w. 424.50 (C₂₇H₂₁N₂O₃).

EXAMPLE 121-(1-Benzo[1,3]dioxol-5-yl-1,3,4,9-tetrahydro-β-carbolin-2-yl)-1-(3H-benzoimidazol-5-yl)methanone

[0180]

[0181] To a solution of Intermediate 2 (0.20 g., 0.68 mmol) and CH₂Cl₂(100 mL) was added 5-benzimidazole carboxylic acid (0.12 g, 1.1 eq.),HOBT (0.12 g, 1.1 eq.), EDCI (0.14 g. 1.1 eq.), and Et₃N (0.10 mL, 1.1eq.) at 25° C. After stirring at rt until the reaction was complete, thereaction mixture was quenched with water (20 mL). The quenched reactionmixture was extracted with CH₂Cl₂, then the organic layer was washedwith brine and dried over MgSO₄. The solvent was removed in vacuo, thenthe residue was purified by flash chromatography, eluting withCH₂Cl₂/MeOH (95:5). Recrystallization from EtOH yielded Example 12 aswhite crystals. m.w. 438.47 (C₂₆H₂₀N₄O₃).

[0182] Examples 13-22 were prepared in a manner similar to Example 1-12.Example 23 further illustrates the preparation of compounds of thepresent invention.

EXAMPLE 13a

[0183]

EXAMPLE 13b

[0184]

EXAMPLE 14

[0185]

EXAMPLE 15

[0186]

EXAMPLE 16

[0187]

EXAMPLE 17

[0188]

EXAMPLE 18

[0189]

EXAMPLE 19

[0190]

EXAMPLE 20

[0191]

EXAMPLE 21

[0192]

EXAMPLE 22

[0193]

EXAMPLE 232-Benzo[b]thiophen-3-yl-1-(1-benzo[1,3]dioxol-5-yl-1,3,4,9-tetrahydro-β-carbolin-2-yl)ethanone

[0194]

[0195] Intermediate 2 was reacted with 3-benzo-thiophene carboxylic acidin CH₂Cl₂ in the presence of HOBT, EDCI, and Et₃N. The reaction productwas isolated and purified by flash chromatography, eluting withCH₂Cl₂/MeOH (90:10). Recrystallization from iPr₂O yielded Example 23 asa white solid. m.w. 466.56 (C₂₈H₂₂N₂O₃S)

[0196] The following Examples 24-44 were prepared by syntheticprocedures similar to the procedures used to prepare Examples 1-23.

EXAMPLE 24

[0197]

EXAMPLE 25

[0198]

EXAMPLE 26

[0199]

EXAMPLE 27

[0200]

EXAMPLE 28

[0201]

EXAMPLE 29

[0202]

EXAMPLE 30

[0203]

EXAMPLE 31

[0204]

EXAMPLE 32

[0205]

EXAMPLE 33

[0206]

EXAMPLE 34

[0207]

EXAMPLE 35

[0208]

EXAMPLE 36

[0209]

EXAMPLE 37

[0210]

EXAMPLE 38

[0211]

EXAMPLE 39

[0212]

EXAMPLE 40

[0213]

EXAMPLE 41

[0214]

EXAMPLE 42

[0215]

EXAMPLE 43

[0216]

EXAMPLE 44

[0217]

EXAMPLE 452-[(1-(2H-benzo[d]1,3-dioxolan-5-yl)-(1R)-(1,2,3,4-tetrahydro-β-carbolin-2-yl)sulfonyl]-5-chloro-3-methylbenzo[b]thiophene

[0218]

[0219] (5-Chloro-3-methylbenzothiophen-2-yl)-sulfonyl chloride was addedto Intermediate 2 to provide Example 45 in 46% yield. mp 139-143° C. NMR(DMSO-d₆) δ: 10.9 (s, 1H), 8.03 (d, J=8.8 Hz, 1H), 7.93 (s, 1H), 7.53(dd, J=2.0, 8.7 Hz, 1H), 7.30 (m, 2H), 7.09 (m, 1H), 6.85-6.95 (m, 2H),6.70 (s, 1H), 6.62 (dd, J=1.5, 8.0 Hz), 6.25 (s, 1H), 6.00 (s, 1H), 5.99(s, 1H), 4.05 (dd, J=5.3, 14.5 Hz, 1H), 3.38-3.40 (m, 1H), 2.70 (dd,J=3.8, 16 Hz), 2.41-2.44 (m, 1H), 2.40 (s, 3H); MS ES+m/e 537.1 (p+1)E/S−m/e 535.1 (p−1).

EXAMPLE 462-(1-Benzo[1,3]dioxol-5-yl-1,3,4,9-tetrahydro-β-carbolin-2-yl)-6.7-dimethoxy-3H-quinazolin-4-one

[0220]

[0221] Example 46 was prepared from Intermediate 2 and the quinazolineIntermediate 8 by the following synthetic procedure. Intermediate 8 wasprepared in accordance with the procedure set forth in J. Miller et al.,J. Med. Chem., 28, p. 12 (1985).

[0222] Quinazolinone Intermediate 8

[0223] A solution of 2,4-dichloro-6,7-dimethoxy-quinazoline (2.12 g,8.20 mmol) in 1 M NaOH (50 mL) and THF (15 mL) was stirred at roomtemperature under an argon blanket for 23 hours. The solution was cooledto 0° C., then acidified to pH 5 with AcOH. The resulting solids werecollected by vacuum filtration and dried in a vacuum oven at 70° C.overnight to provide Intermediate 8 as a pale yellow powder (2.02 g,100%). ¹H NMR (300 MHz, DMSO-d₆) δ: 7.38 (s, 1H), 7.08 (s, 1H), 3.88 (s,3H), 3.85 (s, 3H), 3.50-3.20 (br s, 1H).

Preparation of Example 46

[0224]

[0225] A suspension of Intermediate 2 (3.26 g, 11.2 mmol) andIntermediate 2 (1.69 g, 7.0 mmol) in EtOH (25 mL) was heated in a sealedtube at 110° C. for 2 days. The resulting solids were collected byvacuum filtration, then dissolved in EtOAc (100 mL). The mixture waswashed with 1 M NaOH (100 mL), water (100 mL), and brine (100 mL), driedover Na₂SO₄, and filtered. The solvent was removed under reducedpressure to provide a yellow foam which was purified by flash columnchromatography, eluting with EtOAc/—CH₂Cl₂/MeOH (1:4:0.1), to providethe crude product as a yellow solid. This crude product was purified bya slurry in Et₂O/MeOH, followed by vacuum filtration to provide Example46 as a white solid (1.03 g, 33%): mp 282-290° C.; TLC R_(f) (4:1:0.1CH₂Cl₂/EtOAc/−MeOH=0.36. ¹H NMR (300 MHz, DMSO-d₆) δ: 11.46 (s, 1H),10.99 (s, 1H), 7.46 (d, J=7.53 Hz, 1H), 7.32-7.28 (m, 2H), 7.10-6.96 (m,3H), 6.88-6.71 (m, 4H), 5.98 (d, J=3.74 Hz, 2H), 4.46 (m, 1H), 3.86 (s,3H), 3.79 (s, 3H), 3.40-3.30 (m, 2H), 2.87-2.74 (m, 2H); API MS m/z 497[C₂₈H₂₄N₄P₅+H]⁺. Anal. Calcd. for C₂₈H₂₄N₄O₅: C, 67.73; H, 4.87; N,11.28. Found: C, 67.53; H, 5.08; N, 11.12.

EXAMPLE 47a1-Benzo[1,3]dioxol-5-yl-2-(4-chloro-6,7-dimethoxy-quinazolin-2-yl)-2,3,4,9-tetrahydro-1H-β-carbolineEXAMPLE 47b1-Benzo[1,3]dioxol-5-yl-2-(6,7-dimethoxyquinazolin-2-yl)-2,3,4,9-tetrahydro-1H-β-carboline

[0226] Examples 47a and 47b were prepared from Example 46 by thefollowing synthetic sequence.

Preparation of Example 47a

[0227] Phosphorous oxychloride (0.41 mL, 4.4 mmol) was added slowly to aslurry of Example 46 (0.73 g, 1.5 mmol) and Et₃N (0.41 mL, 2.9 mmol) in1,4-dioxane (10 mL), and the mixture was heated at 100° C. for 3 hours.The cooled reaction mixture was dissolved in CHCl₃ (100 mL), poured intoice water and neutralized with 2M NaOH. The organic layer was collected,washed with water (100 mL), and brine (100 mL), dried over Na₂SO₄, andconcentrated under reduced pressure to provide an orange oil. Thisresidue was purified by flash column chromatography, eluting withhexanes/EtOAc (2:1), to provide Example 47a as a yellow foam (0.80 g,100%). A sample of Example 47a was further purified by a slurry inCH₂Cl₂, followed by vacuum filtration to provide a pale yellow solidwhich was dried overnight under vacuum at 85° C.: mp 231/234° C.; TLCR_(f) (2:1 hexanes/−ethyl acetate)=0.49. ¹H NMR (300 MHz, DMSO-d₆) δ:10.98 (s, 1H), 7.46 (d, J=7.7 Hz, 1H), 7.31 (d, J=7.8 Hz, 1H), 7.17 (s,1H), 7.10-6.97 (m, 3H), 6.90-6.86 (m, 2H), 6.79 (d, J=7.9 Hz, 1H), 5.97(d, J=4.4 Hz, 2H), 4.93-4.89 (m, 1H), 3.95 (s, 3H), 3.88 (s, 3H),3.27-3.23 (m, 2H), 2.86-2.85 (m, 2H) ppm; API MS m/z 515[C₂₈H₂₃ClN₄O₄+H]⁺. Anal. Calcd. for C₂₈H₂₃ClN₄O₄: C, 65.31; H, 4.50; N,10.88. Found: C, 64.92; H, 4.50; N, 10.79.

Preparation of Example 47b

[0228] A mixture of Example 47a (0.52 g, 1.01 mmol), a catalytic amountof 10% palladium on activated carbon (0.32 g, 10% wet), and concentratedammonium hydroxide (1.5 mL) in EtOH (55 mL) was stirred under a hydrogenatmosphere for 12 hours at room temperature. The palladium catalyst wasremoved by vacuum filtration through a plug of Celite, and the resultingfiltrate was concentrated under reduced pressure and purified by flashcolumn chromatography, eluting with hexanes/EtOAc (2:1), to provide thecrude product. This crude product was further purified by triturationwith a hexane/Et₂O/−CH₂Cl₂ mixture to provide Example 47b as a paleyellow solid (0.21 g, 44%): mp 201-204° C.; TLC R_(f) (2:1hexanes/EtOAc)=0.26. ¹H NMR (300 MHz, DMSO-d₆) δ: 10.98 (s, 1H), 9.02(s, 1H), 7.45 (d, J=7.6 Hz, 1H), 7.31 (d, J=7.9 Hz, 1H), 7.24-7.22 (m,2H), 7.09-6.76 (m, 5H), 5.97 (d, J=4.8 Hz, 2H), 5.04-4.99 (m, 1H), 3.93(s, 3H), 3.84 (s, 3H), 3.27-3.21 (m, 2H), 2.86-2.82 (m, 2H) ppm; API MSm/z 481 [C₂₈H₂₄N₄O₄+H]⁺. Anal. Calcd. for C₂₈H₂₄N₄O₄: C, 69.99; H, 5.03;N, 11.66. Found: C, 69.62; H, 5.13; N, 11.26.

[0229] The following Examples 48-87 were prepared by syntheticprocedures analogous to the procedures used to synthesize Examples 1-47.

EXAMPLE 48

[0230]

EXAMPLE 49

[0231]

EXAMPLE 50

[0232]

EXAMPLE 51

[0233]

EXAMPLE 52

[0234]

EXAMPLE 53

[0235]

EXAMPLE 54

[0236]

EXAMPLE 55

[0237]

EXAMPLE 56

[0238]

EXAMPLE 57

[0239]

EXAMPLE 58

[0240]

EXAMPLE 59

[0241]

EXAMPLE 60

[0242]

EXAMPLE 61

[0243]

EXAMPLE 62

[0244]

EXAMPLE 63

[0245]

EXAMPLE 64

[0246]

EXAMPLE 65

[0247]

EXAMPLE 66

[0248]

EXAMPLE 67

[0249]

EXAMPLE 68

[0250]

EXAMPLE 69

[0251]

EXAMPLE 70

[0252]

EXAMPLE 71

[0253]

EXAMPLE 72

[0254]

EXAMPLE 73

[0255]

[0256]

EXAMPLE 74

[0257]

EXAMPLE 75

[0258]

EXAMPLE 76

[0259]

EXAMPLE 77

[0260]

EXAMPLE 78

[0261]

EXAMPLE 79

[0262]

EXAMPLE 80

[0263]

EXAMPLE 81

[0264]

EXAMPLE 82

[0265]

EXAMPLE 83

[0266]

EXAMPLE 84

[0267]

EXAMPLE 85

[0268]

EXAMPLE 86

[0269]

EXAMPLE 87

[0270]

[0271] Compounds of the present invention can be formulated into tabletsfor oral administration. For example, a compound of formula (I) can beformed into a dispersion with a polymeric carrier by the coprecipitationmethod set forth in WO 96/38131, incorporated herein by reference. Thecoprecipitated dispersion then can be blended with excipients, thenpressed into tablets, which optionally are film-coated.

[0272] The compounds of structural formula (I) were tested for anability to inhibit PDE5. The ability of a compound to inhibit PDE5activity is related to the IC₅₀ value for the compound, i.e., theconcentration of inhibitor required for 50% inhibition of enzymeactivity. The IC₅₀ value for compounds pounds of structural formula (I)were determined using recombinant human PDE5.

[0273] The compounds of the present invention typically exhibit an IC₅₀value against recombinant human PDE5 of less than about 50 μM, andpreferably less than about 25 μM, and more preferably less than about 15μm. The compounds of the present invention typically exhibit an IC₅₀value against recombinant human PDE5 of less than about 1 μM, and oftenless than about 0.05 μM. To achieve the full advantage of the presentinvention, a present PDE5 inhibitor has an IC₅₀ of about 0.1 nM to about15 μM.

[0274] The production of recombinant human PDEs and the IC50determinations can be accomplished by well-known methods in the art.Exemplary methods are described as follows:

[0275] Expression of Human PDEs

[0276] Expression in Saccharomyces cerevisiae (Yeast)

[0277] Recombinant production of human PDE1B, PDE2, PDE4A, PDE4B, PDE4C,PDE4D, PDE5, and PDE7 was carried out similarly to that described inExample 7 of U.S. Pat. No. 5,702,936, incorporated herein by reference,except that the yeast transformation vector employed, which is derivedfrom the basic ADH2 plasmid described in Price et al., Methods inEnzymology, 185, pp. 308-318 (1990), incorporated yeast ADH2 promoterand terminator sequences and the Saccharomyces cerevisiae host was theprotease-deficient strain BJ2-54 deposited on Aug. 31, 1998 with theAmerican Type Culture Collection, Manassas, Va., under accession numberATCC 74465. Transformed host cells were grown in 2× SC-leu medium, pH6.2, with trace metals, and vitamins. After 24 hours, YEPmedium-containing glycerol was added to a final concentration of 2XYET/3% glycerol. Approxiately 24 hr later, cells were harvested, washed,and stored at −70° C.

[0278] Human Phosphodiesterase Preparations

[0279] Phosphodiesterase Activity Determinations

[0280] Phosphodiesterase activity of the preparations was determined asfollows. PDE assays utilizing a charcoal separation technique wereperformed essentially as described in Loughney et al. (1996). In thisassay, PDE activity converts [32P]cAMP or ([32P]cGMP to thecorresponding [32P]5′-AMP or [32P]5′-GMP in proportion to the amount ofPDE activity present. The [32P]5′-AMP or [32P]5′-GMP then wasquantitatively converted to free [32P]phosphate and unlabeled adenosineor guanosine by the action of snake venom 5′-nucleotidase. Hence, theamount of [32P]phosphate liberated is proportional to enzyme activity.The assay was performed at 30° C. in a 100 μL reaction mixturecontaining (final concentratrations) 40 mM Tris HCl (pH 8.0), 1 μMZnSO₄, 5 mM MgCl₂₁ and 0.1 mg/mL bovine serum albumin (BSA). PDE enzymewas present in quantities that yield<30% total hydrolysis of substrate(linear assay conditions). The assay was initiated by addition ofsubstrate (1 mM [32P]cAMP or cGMP), and the mixture was incubated for 12minutes. Seventy-five (75) μg of Crotalus atrox venom then was added,and the incubation was continued for 3 minutes (15 minutes total). Thereaction was stopped by addition of 200 μL of activated charcoal (25mg/mL suspension in 0.1 M NaH₂PO₄, pH 4). After centrifugation (750×gfor 3 minutes) to sediment the charcoal, a sample of the supernatant wastaken for radioactivity determination in a scintillation counter and thePDE activity was calculated.

[0281] Purification of PDE5 from S. cerevisiae

[0282] Cell pellets (29 g) were thawed on ice with an equal volume ofLysis Buffer (25 mM Tris HCl, pH 8, 5 mM MgCl₂, 0.25 mM DTT, 1 mMbenzamidine, and 10 μM ZnSO₄). Cells were lysed in a Microfluidizer®(Microfluidics Corp.) using nitrogen at 20,000 psi. The lysate wascentrifuged and filtered through 0.45 μm disposable filters. Thefiltrate was applied to a 150 mL column of Q SEPHAROSE ® Fast-Flow(Pharmacia). The column was washed with 1.5 volumes of Buffer A (20 mMBis-Tris Propane, pH 6.8, 1 mM MgCl₂, 0.25 mM DTT, 10 μM ZnSO₄) andeluted with a step gradient of 125 mM NaCl in Buffer A followed by alinear gradient of 125-1000 mM NaCl in Buffer A. Active fractions fromthe linear gradient were applied to a 180 mL hydroxyapatite column inBuffer B (20 mM Bis-Tris Propane (pH 6.8), 1 mM MgCl₂, 0.25 mM DTT, 10μM ZnSO₄, and 250 mM KCl). After loading, the column was washed with 2volumes of Buffer B and eluted with a linear gradient of 0-125 mMpotassium phosphate in Buffer B. Active fractions were pooled,precipitated with 60% ammonium sulfate, and resuspended in Buffer C (20mM Bis-Tris Propane, pH 6.8, 125 mM NaCl, 0.5 mM DTT, and 10 μM ZnSO₄)The pool was applied to a 140 mL column of SEPHACRYL® S-300 HR andeluted with Buffer C. Active fractions were diluted to 50% glycerol andstored at −20° C.

[0283] The resultant preparations were about 85% pure by SDS-PAGE. Thesepreparations had specific activities of about 3 μmol CGMP hydrolyzed perminute per milligram protein.

[0284] Inhibitory Effect on cGMP-PDE

[0285] cGMP-PDE activity of compounds of the present invention wasmeasured using a one-step assay adapted from Wells et al., Biochim.Biophys. Acta, 384, 430 (1975). The reaction medium contained 50 mMTris-HCl, pH 7.5, 5 mM magnesium acetate. 250 μg/ml 5′-Nucleotidase, 1mM EGTA, and 0.15 μM 8-[H³]-cGMP. Unless otherwise indicated, the enzymeused was a human recombinant PDE5 (ICOS Corp., Bothell, Wash.).

[0286] Compounds of the invention were dissolved in DMSO finally presentat 2% in the assay. The incubation time was 30 minutes during which thetotal substrate conversion did not exceed 30%.

[0287] The IC₅₀ values for the compounds examined were determined fromconcentration-response curves typically using concentrations rangingfrom 10 nM to 10 μM. Tests against other PDE enzymes using standardmethodology showed that compounds of the invention are selective for thecGMP-specific PDE enzyme.

[0288] Biological Data

[0289] The compounds according to the present invention were typicallyfound to exhibit an IC₅₀ value of less than 500 nM (i.e., 0.5 μM). Invitro test data for representative compounds of the invention is givenin the following table: TABLE 1 In vitro Results Example PDE5 IC₅₀ (μM) 1 0.566  2 0.71  3 0.44¹⁾  4 0.05¹⁾  5 0.2  6 0.67  7 0.55  8 0.19  90.44 10 0.76 11 0.44 12 0.18¹⁾  13a 0.48  13b 0.02 14 0.2¹⁾ 15 0.001¹⁾16 0.07¹⁾ 17 0.25¹⁾ 18 0.11 19 0.25 20 0.42 21 0.13 22 0.08 23 0.36 240.03 25 0.04 26 0.9 27 0.04 28 0.12 29 0.3 30 0.06 31 0.04 32 0.48 330.2 34 0.46 35 0.41 36 0.11 37 0.04 38 0.03 39 0.4 40 0.32 41 0.24 420.85 43 0.29 44 0.49 45 0.22 46 0.005  47a 0.027  47b 0.005 48 0.02 490.01 50 0.78 51 0.03 52 0.29 53 0.07 54 0.56 55 0.02 56 0.04 57 0.06 580.03 49 0.04 60 0.07 61 0.04 62 0.05 63 0.04 64 0.76 65 0.02 66 0.34 670.07 68 0.02 69 0.009 70 0.02 71 0.02 72 0.01 73 0.03 74 0.04 75 0.00776 0.01 77 0.004 78 0.06 79 0.004 80 0.05 81 0.003 82 0.005 83 0.082 840.309 85 0.835 86 0.90 87 1.01

[0290] Obviously, many modifications and variations of the invention ashereinbefore set forth can be made without departing from the spirit andscope thereof, and, therefore, only such limitations should be imposedas are indicated by the appended claims.

What is claimed is:
 1. A compound having a formula

wherein R⁰, independently, is selected from the group consisting ofhalo, C₁₋₆alkyl, aryl, heteroaryl, C₃-acycloalkyl, C₃₋₈heterocycloalkyl,C₃₋₈cycloalkylQ, C(═O)R^(a), OC(═O)R^(a), C(═O)OR^(a),C₁₋₄alkyleneNR^(a)R^(b), C₁₋₄alkyleneHet, C₁₋₄alkyleneC(═O)OR^(a),C(═O)NR^(a)SO₂R^(c), C(═O)C₁₋₄alkyleneHet, C(═O)NR^(a)R^(b),C(═O)NR^(b)R^(c), C(═O)—NR^(a)C₁₋₄alkyleneOR^(b),C(═O)NR^(a)C₁₋₄alkyleneHet, OR^(a), OC₁₋₄-alkyleneC(═O)OR^(a),OC₁₋₄alkyleneNR^(a)R^(b), OC₄alkyleneHet, OC₁₋₄alkyleneOR^(a),OC₁₋₄alkyleneNR^(a)C(═O)OR^(b), NR^(a)R^(b), NR^(b)R^(c),NR^(a)C₁₋₄alkyleneNR^(a)R^(b), NR^(a)C(═O)R^(b), NR^(a)C(═O)NR^(a)R^(b),N(SO₂C₁₋₄alkyl)₂, NR^(a)(SO₂C₁₋₄alkyl), nitro, trifluoromethyl,trifluoromethoxy, cyano, SO₂NR^(a)R^(b), SO₂R^(a), SOR^(a), SR^(a), andOSO₂CF₃; R1 is selected from the group consisting of optionallysubstituted aryl, optionally substituted heteroaryl, an optionallysubstituted C₃₋₈cycloalkyl ring, an optionally substitutedC₃₋₈heterocycloalkyl ring, an optionally substituted bicyclic ring

wherein the fused ring B is a 5- or 6-membered ring, saturated orpartially or fully unsaturated, and comprises carbon atoms andoptionally one to three heteroatoms selected from oxygen, sulfur, andnitrogen, hydrogen, C₁₋₆alkyl, arylC₁₋₃alkyl, C₁₋₃-alkenylenearyl,haloC₁₋₆alkyl, C₁₋₄alkyleneC(═O)OR^(a), C₁₋₄alkyleneC(═O)NR^(a)R^(b),C₃₋₈cycloalkyl, C₃₋₈cycloalkenyl, C₃₋₈heterocycloalkenyl,C₁₋₄alkyleneHet, C₁₋₄alkylene-QR^(a), C₂₋₆-alkenyleneQR^(a),C₁₋₄alkyleneQC₁₋₄alkyleneQR^(a),

and a spiro substituent having a structure

 R² is selected from the group consisting of hydrogen, C₁₋₆alkyl,C₃₋₈cycloalkyl, C₃₋₈heterocycloalkyl, C₂₋₆alkenyl, C₁₋₃alkylenearyl,arylC₁₋₃alkyl, aryl, heteroaryl, C(═O)R^(a), C(═O)NR^(a)R^(b),C(═O)NR^(b)R^(c), C(═S)—NR^(a)R^(b), C(═S)NR^(b)R^(c), OR^(a),NR^(a)R^(b), NR^(b)R^(c), SO₂R^(a), SO₂NR^(a)R^(b), S(═O)R^(a),S(═O)NR^(a)R^(b), C(═O)NR^(a)C₁₋₄alkyleneOR^(a),C(═O)—NR^(a)C₁₋₄alkyleneHet, C(═O)C₁₋₄alkylenearyl,C(═O)C₁₋₄-alkyleneheteroaryl, C₁₋₄alkylenearyl, C₁₋₄alkylene-heteroaryl,C₁₋₄alkyleneHet, C₁₋₄alkyleneC(═O)C₁₋₄-alkylenearyl,C₁₋₄alkyleneC(═O)C₁₋₄alkyleneheteroaryl, C₁₋₄alkyleneC(═O)Het,C₁₋₄alkyleneC(═O)NR^(b)R^(c), C₁₋₄alkyl-eneOR^(a),C₁₋₄alkyleneNR^(a)C(═O)R^(a), C₁₋₄alkyleneOC₁₋₄alkyl-eneOR^(a),C₁₋₄alkyleneNR^(b)R^(c), C₁₋₄alkyleneC(═O)OR^(a), andC₁₋₄alkyleneOC₁₋₄alkyleneC(═O)OR^(a); R³ is selected from the groupconsisting of hydrogen, C₁₋₆alkyl, haloC₁₋₆alkyl, aryl, heteroaryl,arylC₁₋₃alkyl, heteroarylC₁₋₃alkyl, C₁₋₃alkylenearyl, C₁₋₃alkyleneHet,C₃₋₈cycloalkyl, and C₃₋₈heterocycloalkyl; Y is selected from the groupconsisting of C(═O), C(═O)Z, SO, SO₂, C(═S), C(R^(a))₂, andCR^(a)═CR^(a); Z is (CH₂)_(t) or C≡C; A is aryl or heteroaryl and isselected from the group consisting of optionally substituted 5- or6-membered aromatic rings and optionally substituted fused bicyclic ringsystems, either carbocyclic or containing at least one heteroatomselected from the group consisting of oxygen, nitrogen, and sulfur, andcontaining at least one aromatic ring; R⁴ is selected from the groupconsisting of hydrogen, C₁₋₆alkyl, aryl, heteroaryl, halo, C(═O)OR^(b),NHC(═O)Cl₃alkyleneN(R^(b))₂, NO₂, C(═O)OR^(b), OR^(b), CF₃, OR^(a), CN,OC(═O)R^(b), arylOR^(b), Het, NR^(a)C(═O)C₁₋₃alkyleneC(═O)—OR^(a),arylOC₁₋₃alkyleneNR^(a)R^(b), arylOC(═O)R^(a), C₁₋₄alkylene-C(═O)OR^(b),OC₁₋₄alkyleneC(═O)OR^(b), C₁₋₄alkyleneOC₁₋₄-alkyleneC(═O)OR^(b),C(═O)NR^(b)SO₂R^(c), C₁₄alkyleneNR^(b)R^(c), C₂₋₆alkenyleneNR^(b)R^(c),C(═O)NR^(b)C₁₋₄alkyleneOR^(b), C(═O)—NR^(b)C₁₋₄alkyleneHet,OC₂₋₄alkyleneNR^(b)R^(c), OC₁₋₄alkylene-CH(OR^(b))CH₂NR^(b)R^(c),OC₁₋₄alkyleneHet, OC₂₋₄alkyleneOR^(b), OC₂₋₄alkyleneNR^(b)C(═O)OR^(c),NR^(b)C₁₋₄alkyleneNR^(b)R^(c), NR^(b)C(═O)—R^(c),NR^(b)C(═O)NR^(b)R^(c), N(SO₂C₁₋₄alkyl)₂, NR^(b)(SO₂C₁₋₄alkyl)SO₂NR^(b)R^(c), OSO₂CF₃, C(═O)R^(b), C₁₋₃alkylenearyl, C₁₄-alkyleneHet,C₁₋₆alkyleneOR^(b), C₁₋₃alkyleneN(R^(b))₂, NR^(b)R^(c),C(═O)NR^(b)R^(c), NHC(═O)C₁₋₃alkylenearyl,NHC(═O)C₁₋₃alkyleneheteroaryl, C₃₋₈cycloalkyl, C₃₋₈heterocycloalkyl,arylOC₁₋₃alkyleneN(R^(b))₂, arylOC(═O)R^(b),NHC(═O)C₁₋₃-alkyleneC₃₋₈heterocycloalkyl, NHC(═O)C₁₋₃alkyleneHet,NHC(═O)haloC₁₋₆alkyl, and

R⁵, independently, is selected from the group consisting of halo,NR^(a)R^(b), NO₂, C₁₋₆alkyl, oxo, and OR^(a); or R⁴ and R⁵ are takentogether to form a 3- or 4-membered alkylene or alkenylene chaincomponent of a 5- or 6-membered ring, optionally containing at least oneheteroatom; R^(a) is selected from the group consisting of hydrogen,C₁₋₆alkyl, cyano, aryl, arylC₁₋₃alkyl, C₁₋₃-alkylenearyl, heteroaryl,heteroarylC₁₋₃alkyl, and C₁₋₃alkyleneheteroaryl; R^(b) is selected fromthe group consisting of hydrogen, C₁₋₆alkyl, C₃₈cycloalkyl,C₁₋₃alkyleneN(R^(a))₂, aryl, arylC₁₋₃alkyl, C₁₋₃alkylenearyl,heteroaryl, heteroarylC₁₋₃alkyl, and C₁₋₃alkyleneheteroaryl; R^(c) isselected from the group consisting of hydrogen, C₁₋₆alkyl, aryl,heteroaryl, arylC₁₋₃alkyl, heteroarylC₁₋₃alkyl, C₁₋₃alkyleneN(R^(a))₂,C₁₋₆alkylenearyl, C₁₋₆alkyleneHet, haloC₁₋₆alkyl, C₃₋₈cycloalkyl,C₃₋₈heterocycloalkyl, Het, C₁₋₃alkyleneheteroaryl,C₁₋₆alkyleneC(═O)OR^(a), and C₁₋₃alkyleneC₃₋₈heterocycloalkyl; or R^(b)and R^(c) are taken together to form a 5- or 6-membered ring, optionallycontaining at least one heteroatom; Q is O, S, or NR^(d); C is O, S, orNR^(d); D is O, S, or NR^(a); E is CR^(a) or N; F is CR^(a), C(R^(a))₂,or NR^(d); R^(d) is null or is selected from the group consisting ofhydrogen, C₁₋₆alkyl, aryl, heteroaryl, arylC₁₋₃alkyl,heteroarylC₁₋₃alkyl, C₁₋₃alkylenearyl, and C₁₋₃alkyleneheteroaryl; Hetis a 5- or 6-membered heterocyclic ring, saturated or partially or fullyunsaturated, containing at least one heteroatom selected from the groupconsisting of oxygen, nitrogen, and sulfur, and optionally substitutedwith C₁₋₄alkyl or C(═O)OR^(a); n is 0 or 1; p is 0, 1, 2, or 3; q is 0,1, 2, 3, or 4; t is 1, 2, 3, or 4; and pharmaceutically acceptable saltsand solvates thereof.
 2. The compound of claim 1 represented by theformula

wherein R¹ is selected from the group consisting of optionallysubstituted aryl, optionally substituted heteroaryl, an optionallysubstituted bicyclic ring

wherein the fused ring B is a 5- or 6-membered ring, saturated orpartially or fully unsaturated, and comprises carbon atoms andoptionally one to three heteroatoms selected from oxygen, sulfur, andnitrogen; Y null or is selected from the group consisting of C(═O),C(═O)C≡C, C(═O)(CH₂)_(t), SO₂, and C(═S); A is aryl or heteroaryl and isselected from the group consisting of optionally substituted 5- or6-membered aromatic rings and optionally substituted fused bicyclic ringsystems, either carbocyclic or containing at least one heteroatomselected from the group consisting of oxygen, nitrogen, and sulfur, andcontaining at least one aromatic ring; R⁴ is selected from the groupconsisting of hydrogen, C₁₋₆alkyl, aryl, heteroaryl, halo, C(═O)OR^(b),NHC(═O)C₁₋₃alkyleneN(R^(b))₂, N₂, C(═O)OR^(b), OR^(b), CF₃, OR^(a), CN,OC(═O)R^(b), arylOR^(b), Het, NR^(a)C(═O)C₁₋₃alkyleneC(═O)—OR^(a),arylOC₁₋₃alkyleneNR^(a)R^(b), arylOC(═O)R^(a), C₁₋₄alkyleneC(═O)OR^(b),OC₁₋₄alkyleneC(═O)OR^(b), C(═O)NR^(b)SO₂R^(c), C₁₋₄alkyleneNR^(b)R^(c),C₂₋₆alkenyleneNR^(b)R^(c), C(═O)NR^(b)C₁₋₄alkyleneOR^(b),NR^(b)C₁₋₄alkyleneNR^(b)R^(c), NR^(b)C(═O)R^(c), NR^(b)C(═O)NR^(b)R^(c),OSO₂CF₃, C(═O)R^(b), C₁₋₃alkylenearyl, C₁₋₄alkyleneHet,C₁₋₆alkyleneOR^(b), C₁₋₃alkyleneN(R^(b))₂, NR^(b)R^(c),C(═O)NR^(b)R^(c), NHC(═O)C₁₋₃alkylenearyl,NHC(═O)C₁₋₃alkyleneheteroaryl, NHC(═O)C₁₋₃alkyleneHet,NHC(═O)haloC₁₋₆alkyl, and

 R⁵, independently, is selected from the group consisting of halo,NR^(a)R^(b), NO₂, C₁₋₆alkyl, oxo, and OR^(a);  R^(a) and R^(b),independently, are selected from the group consisting of hydrogen,C₁₋₆alkyl, aryl, arylC₁₋₃alkyl, C₁₋₃alkylenearyl, heteroaryl,heteroarylC₁₋₃alkyl, and C₁₋₃alkyleneheteroaryl;  R^(c) is selected fromthe group consisting of hydrogen, C₁₋₆alkyl, aryl, heteroaryl,arylC₁₋₃alkyl, heteroarylC₁₋₃alkyl, C₁₋₃alkyleneN(R^(a))₂,C₁₋₆alkylenearyl, C₁₋₆alkyleneHet, haloC₁₋₆alkyl, C₃₋₈cycloalkyl,C₃₋₈heterocycloalkyl, Het, C₁₋₃alkyleneheteroaryl,C₁₋₆alkyleneC(═O)OR^(a), and C₁₋₃alkyleneC₃₋₈heterocycloalkyl;  or R^(b)and R^(c) are taken together to form a 5- or 6-membered ring, optionallycontaining at least one heteroatom;  Het is a 5- or 6-memberedheterocyclic ring, saturated or partially or fully unsaturated,containing at least one heteroatom selected from the group consisting ofoxygen, nitrogen, and sulfur, and optionally substituted with C₁₋₄alkylor C(═O)OR^(a);  p is 0, 1, 2, or 3;  t is 1, 2, 3, or 4;  andpharmaceutically acceptable salts and solvates thereof.
 3. The compoundof claim 1 represented by the formula

and pharmaceutically acceptable salts and. hydrates thereof.
 4. Thecompound of claim 1 wherein q is
 0. 5. The compound of claim 1 whereinR⁰ is selected from the group consisting of C₁₋₆alkyl, aryl, heteroaryl,C₃₋₈heterocycloalkyl, OR^(a), C(═O)OR^(a), C₁₋₄alkyleneNR^(a)R^(b),OC(═O)R^(a), C(═O)R^(a), NR^(b)R^(c), C₃₋₈cycloalkyl, C₃₋₈cycloalkylQ,C(═O)NR^(a)R^(b), and C(═O)NR^(b)R^(c).
 6. The compound of claim 1wherein R¹ is selected from the group consisting of C₁₋₄alkyleneQR^(a),C₁₋₄alkyleneQC₁₋₄alkyleneQR^(a), C₃₋₈cycloalkyl, C₃₋₈cycloalkenyl,C₁₋₆alkyl,


7. The compound of claim 1 wherein R¹ is the optionally substitutedbicyclic ring


8. The compound of claim 7 wherein R¹ is

and wherein m is an integer 1 or 2, and G, independently, are C(R^(a))₂,O, S, or NR^(a).
 9. The compound of claim 1 wherein R¹ is selected fromthe group consisting of

—CH₂OR^(a), —OCH₂OR^(a),


10. The compound of claim 1 wherein the R² group is selected from thegroup consisting of hydrogen, aryl, heteroaryl, OR^(a), NR^(a)R^(b),NR^(b)R^(c), C₁₋₄alkyleneHet, C₁₋₄alkyleneheteroaryl, C₁₋₄alkylenearyl,C₁₋₄alkyleneC(═O)C₁₋₄alkylenearyl, C₁₋₄alkyleneC(═O)OR^(a),C₁₋₄alkyleneC(═O)NR^(b)R^(c), C₁₋₄alkyleneC(═O)Het,C₁₋₄alkyleneNR^(b)R^(c), C₁₋₄alkyleneNR^(a)C(═O)R^(a), andC₁₋₄alkyleneOC₁ ₄-alkyleneOR^(a).
 11. The compound of claim 1 wherein Ais selected from the group consisting of phenyl, furanyl, thienyl,pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl,isothiazolyl, 1,2,3-oxadiazolyl, 1,2,3-triazolyl, 1,3,4-thiadizolyl,1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl,1,2,3,4-oxatriazolyl, 1,2,3,5-oxatriazolyl, pyridinyl, pyridazinyl,pyrimidinyl, pyrazinyl, 1,3,5-triazinyl, 1,2,4-triazinyl,1,2,3-triazinyl, indolizinyl, indolyl, isoindolyl, benzo[b]-furanyl,benzo[b]thienyl, 1H-indazolyl, benzimidazolyl, benzthiazoyl, purinyl,4H-quinolizinyl, quinolinyl, isoquinolinyl, indenyl, and naphthyl. 12.The compound of claim 1 wherein R⁴ is selected from the group consistingof hydrogen, C₁₋₆alkyl, aryl, heteroaryl, halo, C(═O)OR^(b),NHC(═O)—C₁₋₃alkyleneN(R^(b))₂, NO₂, C(═O)OR^(b), OR^(b), CF₃, OR^(a),CN, OC(═O)R^(b), arylOR^(b), Het, NR(═O)C₁₋₃alkyleneC(═O)OR^(a),arylOC₁₋₃alkyleneNR^(a)R^(b), arylOC(═O)R^(a), C₁₋₄alkyleneC(═O)—OR^(b),OC₁₋₄alkyleneC(═O)OR^(b), C(═O)NR^(b)SO₂R^(c), C₁₋₄alkylene-NR^(b)R^(c),C₂₋₆alkenyleneNR^(b)R^(c), C(═O)NR^(b)C₁₋₄alkyleneOR^(b),NR^(b)C₁₋₄alkyleneNR^(b)R^(c), NR^(b)C(═O)R^(c)NR^(b)C(═O)NR^(b)R^(c),OSO₂CF₃, C(═O)R^(b), C₁₋₃alkylenearyl, C₁₋₄alkyleneHet,C₁₋₆alkyleneOR^(b), C₁₋₃alkyleneN(R^(b))₂, NR^(b)R^(c),C(═O)NR^(b)R^(c), NHC(═O)C₁-C₃alkylenearyl, C₃₋₈cycloalkyl,C₃₋₈heterocycloalkyl, NHC(═O)C₁₋₃alkyleneHet, NHC(═O)haloC₁₋₆alkyl, and


13. The compound of claim 1 wherein R³ is selected from the groupconsisting of hydrogen, C₁₋₆alkyl, aryl, and heteroaryl.
 14. Thecompound of claim 1 wherein q is 0 or R⁰ is selected from the groupconsisting of halo, methyl, trifluoromethyl, and trifluoromethoxy; R¹ isselected from the group consisting of

R² is selected from the group consisting of hydrogen, C₁₋₆alkyl,C(═O)NR^(b)R^(c), and C₁₋₄alkyleneHet; R³ is selected from the groupconsisting of hydrogen, C₁₋₆-alkyl, aryl, and heteroaryl; Y is null, orY is selected from the group consisting of C(═O), C(═O)C≡C, C(═O)CH₂,C(═O)CH₂CH₂, and SO₂; A is

 R⁴ is selected from the group consisting of H, NHC(═O)CH₃, N(CH₃)₂,C(═O)NH₂, NHCH₃, NO₂, NH₂, Br, C(═O)CH₃, OCH₃, CH₂OCH₃,NHC(═O)CH₂N(CH₃)₂, CH₂N(CH₃)₂, CH₃, Cl, NHC(═O)CH₂CO₂H,

p is 0 or groups, independently, are selected from the group consistingof CH₃, Cl, oxo, and OCH₃.
 15. The compound of claim 14 wherein R² ishydrogen and R³ is hydrogen.
 16. A compound selected from the groupconsisting of1-(2H-benzo[d]1,3-dioxolan-5-yl)(1,2,3,4-tetrahydro-β-carbolin-2-yl)-2-naphthylketone;1-(2H-benzo[d]1,3-dioxolan-5-yl)(1R)(1,2,3,4-tetrahydro-β-carbolin-2-yl)2-naphthylketone;1-(1-benzo[1,3]dioxol-5-yl-1,3,4,9-tetrahydro-β-carbolin-2-yl)-1-phenylmethanone;N-{4[1-(1-benzo[1,3]dioxol-5-yl-1,3,4,9-tetrahydro-β-carboline-2-yl)-methanoyl]phenyl}acetamide;1-(1-benzo[1,3]dioxol-5-yl-1,3,4,9-tetrahydro-β-carbolin-2-yl)-1-(4-methylaminophenyl)methanone;1-(1-benzo[1,3]dioxol-5-yl-1,3,4,9-tetrahydro-β-carbolin-2-yl)-1-(4-dimethylaminophenyl)methanone;4-[1-(1-benzo[1,3]dioxol-5-yl-1,3,4,9-tetrahydro-β-carbolin-2-yl)methanoyl]benzamide;1-(1-benzo[1,3]dioxol-5-yl-1,3,4,9-tetrahydro-β-carbolin-2-yl)-3-phenylpropynone;3-(2-aminophenyl)-1-(1-benzo[1,3]dioxol-5-yl-1,3,4,9-tetrahydro-β-carbolin-2-yl)propan-1-one;N-{4-[1-(1-benzo[1,3]dioxol-5-yl-1,3,4,9-tetrahydro-carbolin-2-yl)methanoyl]phenyl}-2-phenylacetamide;1-(1-benzo[1,3]dioxol-5-yl-1,3,4,9-tetrahydro-β-carbolin-2-yl)-3-phenylpropan-1-one;1-(1-benzo[1,3]dioxol-5-yl-1,3,4,9-tetrahydro-β-carbolin-2-yl)-1-(3H-benzoimidazol-5-yl)methanone;2-benzo[b]thiophen-3-yl-1-(1-benzo[1,3]dioxol-5-yl-1,3,4,9-tetrahydro-β-carbolin-2-yl)ethanone;2-[(1-(2H-benzo[d]1,3-dioxolan-5-yl)-(1R)-(1,2,3,4-tetrahydro-β-carbolin-2-yl)sulfonyl]-5-chloro-3-methylbenzo[b]thiophene;2-(1-benzo[1,3]dioxol-5-yl-1,3,4,9-tetrahydro-β-carbolin-2-yl)-6,7-dimethoxy-3H-quinazolin-4-one;1-benzo[1,3]dioxol-5-yl-2-(4-chloro-6,7-dimethoxy-quinazolin-2-yl)-2,3,4,9-tetrahydro-1H-β-carboline;1-benzo[1,3]dioxol-5-yl-2-(6,7-dimethoxyquinazolin-2-yl)-2,3,4,9-tetrahydro-1H-β-carboline;and a pharmaceutically acceptable salt or solvate thereof.
 17. Acompound selected from the group consisting of Examples 13a, 13b, 14-22,24-44, and 48-87 as disclosed herein, and a pharmaceutically acceptablesalt or solvate thereof.
 18. A pharmaceutical composition comprising acompound of claim 1, together with a pharmaceutically acceptable diluentor carrier.
 19. A method of treating a male or female animal in thetreatment of a condition where inhibition of a cGMP-specific PDE is of atherapeutic benefit comprising treating said animal with an effectiveamount of a pharmaceutical composition comprising a compound of claim 1,together with a pharmaceutically acceptable diluent or carrier.
 20. Themethod of claim 19 wherein the condition is male erectile dysfunction.21. The method of claim 20 wherein the treatment is an oral treatment.22. The method of claim 19 wherein the condition is female arousaldisorder.
 23. The method of claim 22 wherein the treatment is an oraltreatment.
 24. The method of claim 19 wherein the condition is selectedfrom the group consisting of stable angina, unstable angina, variantangina, hypertension, pulmonary hypertension, chronic obstructivepulmonary disease, malignant hypertension, pheochromocytoma, acuterespiratory distress syndrome, congestive heart failure, acute renalfailure, chronic renal failure, atherosclerosis, a condition of reducedblood vessel patency, a peripheral vascular disease, a vasculardisorder, thrombocythemia, an inflammatory disease, myocardialinfarction, stroke, bronchitis, chronic asthma, allergic asthma,allergic rhinitis, glaucoma, peptic ulcer, a gut motility disorder,postpercutaneous transluminal coronary angioplasty, carotid angioplasty,post-bypass surgery graft stenosis, osteoporosis, preterm labor, benignprostatic hypertrophy, and irritable bowel syndrome.
 25. A method oftreating a condition where inhibition of a cGMP-specific PDE is oftherapeutic benefit, in a human or a nonhuman animal body, comprisingadministering to said body a therapeutically effective amount of acompound of claim
 1. 26. A method for the curative or prophylactictreatment of male erectile dysfunction or female arousal disorder,comprising administration of an effective dose of a compound of claim 1,and pharmaceutically acceptable salts and solvates thereof, to ananimal.
 27. Use of a compound of claim 1 for the manufacture of amedicament for the curative or prophylactic treatment of a conditionwhere inhibition of a cGMP-specific PDE is of a therapeutic benefit.